Novel opiate compounds, methods of making and methods of use

ABSTRACT

The present invention relates to a class of nitrogen-containing heterocyclic compounds which bind to opioid receptors. The inventive compounds can be used to treat a variety of disease states which involve the opioid receptors.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to novel opioid receptorantagonists and agonists, methods of making these compounds, and methodsof use.

[0003] 2. Description of the Background

[0004] The opioid receptor system has been extensively studied over thepast eight decades, driven primarily by a search for analgesics that donot possess the abuse potential associated with morphine. While thesestudies were unsuccessful, our understanding of the opioid system hasincreased tremendously. A significant breakthrough in our understandingof this system came about as a realization that the pharmacology ofopioids is receptor based. From this vantage point, the focus ofresearch turned to identifying receptor subtypes with the ultimate goalof assigning specific physiological function to individual receptors.Today, the receptor system is known to be composed of the three distinctsubtypes OP₁, OP₂, and OP₃ (delta, kappa and mu), as each of these havebeen cloned and been shown to derive from three different chromosomes.For a discussion of opioid receptors, see Kirk-Othmer Encyclopedia ofChemical Technology, Volume 17, Fourth Edition, 1996, pp. 858-881. Thereis however less however as to the number of subtypes within each of themain branches and while much has been learned along these lines, theprocess of assigning function to subtypes is still an area of activeinvestigation.

[0005] The opioid receptor system has been extensively studied over thepast eight decades driven primarily by a search for analgesics that donot possess the abuse potential associated with morphine. While thiseffort has been unsuccessful to date, recent studies have highlightedthe delta opioid receptor system as holding the greatest potential forsuccess. Principally, agonists acting through the delta opioid receptorhave been shown to modulate pain while minimizing many of theside-effects associated with morphine which acts primarily at the muopioid receptor. These unwanted side-effects include physicaldependence, respiratory depression, and gastrointestinal motilityproblems. These findings have led to a dramatic increase in the researchefforts directed toward the production of potent, highly delta receptorselective agonists. The bulk of this effort has been in discoveringsmall molecules as opposed to peptides due to their enhanced stabilityin vivo and their ability to penetrate the central nervous system.

[0006] I.

[0007] The discovery of potent, highly receptor-selective opioid pureantagonists has been a goal of medicinal chemists for many years.^(1,2)As molecular probes, antagonists have served as useful tools in thestudy of both the structure as well as the physiological functions ofthe highly complex opioid receptor system. Much has been accomplished asevidenced by the elegant work of Portoghese and coworkers over the pastdecade which ultimately has led to the discovery of the naltrexone-basedkappa and delta receptor subtype-selective antagonistsnorbinaltorphimine³ (1, nor-BNI) and naltrindole⁴ (2, NTI),respectively. Following Portoghese's lead, workers at SmithKline Beechamrecently reported that the octahydroisoquinoline (3, SB 205588) was asecond-generation, highly potent and selective delta antagonist formallyderived from naltrindole fragmentation.⁵ One specific research aim hasbeen the discovery of opioid receptor selective reversibly bindingligands from the N-substituted(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4a) class ofcompounds that display pure antagonist activity.⁶ These compounds willbe useful as molecular probes for the opioid receptor as well aspotential drug candidates for the treatment of substance abuse and otherCNS disorders.⁷ While mu antagonists have for years been used in drugabuse therapy, recent findings suggest that kappa antagonists couldprovide a more effective, long-lasting treatment strategy.⁸ A greatvariety of N-substituted derivatives of 4a has been prepared, but untilthe recent demonstration of mu selectivity for 5a,⁹ none had shownselectivity between the opioid receptor subtypes. Since the pureantagonist activity of these compounds is not dependent on theN-substituent, multiple changes to this part of the molecule would beexpected to affect binding affinity and possibly receptor selectivitybut not alter its fundamental antagonist character. This featuredistinguishes this class of antagonist from the morphone-basedcompounds, which display pure antagonist behavior only withN-substituents such as allyl or cyclopropylmethyl but not methyl, ethyl,or phenethyl.¹⁰ It is currently believed that the N-substituent in 4ainteracts with a lipophilic binding domain which has been described aseither very large or quite malleable since a multitude of differenttypes of N-substituent changes provided ligands displaying high bindingaffinity.¹¹ It has also been determined that maximum potency andselectivity for the mu opioid receptor is achieved when theN-substituent incorporates a lipophilic entity (phenyl or cyclohexylring) separated from the piperidine nitrogen by three atoms asillustrated by compounds 5a-d.^(9,11) The synthesis of K-selectivecompounds remains an important goal.

[0008] II.

[0009] Derivatives of N-substituted(±)-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, such as 6 and 7,are known to posses nonselective potent opioid pure antagonistactivity.¹²⁻¹⁶ Early investigations of the phenylpiperidine class ofopioid antagonists identified the 3-methyl substituent and its transrelative relationship to the 4-substituent as being both necessary andsufficient to impart antagonist activity to the agonist4-(3-hydroxyphenyl)piperidine.¹² This feature distinguished thephenylpiperidines from the oxymorphones which rely on particularN-substituents (i.e. allyl, cyclopropylmethyl) for expression of opioidantagonist activity.¹⁷ Further studies demonstrated that theN-substituent in the phenylpiperidine antagonists controls their potencyand efficacy.¹⁵ Accordingly, there remains a need for compounds whichhave similar therapeutic effects as thetrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, but are based ondifferent structural elements.

[0010] III.

[0011] Numerous structural types of opioid agonists have beendiscovered, and several such as methadone, meperidine, fentanyl, andpentazocine as well as others have become important drugs for thetreatment of pain.¹⁰ However, there are only a few structural types thatshow, potent, opioid pure antagonist activity.^(10,7) A resurgence inheroin use in recent years coupled with the demonstrated effectivenessof opioid antagonists for the treatment of other substances of abuse hasspurred new interest in the development of novel antagonists for opioidreceptors.¹⁶

[0012] The oxymorphone-related compounds such as naloxone (8a) andnaltrexone (8b), where the antagonist activity is dependent upon theN-substituent, have received considerable attention over the past fewdecades.¹⁰ For example, pioneering studies by Portoghese and coworkerslead to the development of the prototypical kappa and delta opioidreceptor antagonists, norbinaltorphimine (1, nor-BNI) and naltrindole(2, NTI). In contrast, the N-substitutedtrans-3,4-dimethyl-(3-hydroxyphenyl)piperidine (9a-d) class of pureantagonist has received relatively little attention. Studies with theN-methyl analog 9a as well as many other N-substituted analogs such as9b, 9c (LY255582), and 9d showed that the pure antagonist activity wasdependent on the 3-methyl substituent and its trans relativerelationship to the 4-methyl substituent on the piperidine ring and,unlike the oxymorphone class, was independent of the nature of theN-substituent.^(7,16,17,6,13,14) Interestingly, the 3,4-dimethyl cisisomer 9e was found to be a mixed agonist-antagonist. May andcoworkers¹⁸ reported that 2,9α-dimethyl-5-(3-hydroxyphenyl)morphan(10a), which has the 9-methyl group in a configuration comparable to thecis-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (9e) with the5-(3-hydroxyphenyl) group locked in an equatorial conformation relativeto the piperidine ring in the morphan structure, was a weak but pureantagonist.

[0013] Neither 2,9β-dimethyl-5-(3-hydroxyphenyl)morphan (10b) nor2,4β-dimethyl-5-(3-hydroxyphenyl)morphan (10 g) have not been reported,due to a lack of synthetic accessibility to these structural isomers.Accordingly, the successful synthetic preparation of 2,9β-morphans and2,4β-morphans remains an important goal of in the field opioidreceptor-binding compounds.

[0014] IV.

[0015] In search of analgesics possessing a reduced side-effect profilerelative to morphine, much effort has been expended towards findingopioids which operate via δ or κ opioid receptors as opposed to the μopioid receptor which meditates the actions of morphine and itscongeners.¹⁰ BW373U86 (11)¹⁹ and SNC-80 (12)²⁰ represent one class ofopioid agonists discovered to be selective for the δ opioid receptor.Due to the lack of a clear opioid message substructure (i.e., a tyraminecomponent similar to the enkephalins), compounds 11 and 12 have beenreferred to as non-classical opioid ligands.⁵ The piperazine subunit of11 and 12 is not commonly found in compounds showing activity at theopioid receptors. In contrast, piperidine ring compounds are found inmany different classes of opioids.²⁷ If the internal nitrogen atom incompounds 11 or 12 is transposed with the benzylic carbon, piperidinering analogs such as 13 would be obtained. Even though there are commonstructural elements between structures 11 or 12 and 13, the expecteddifference between in basicity between the piperidinyl amino group of 11or 12 and the di-phenyl substituted amine of 13 is sufficient such thatit cannot be predicted whether similarity to suggest that 13 wouldinteract with opioid receptors similar to 11 or 12. It is alsointeresting to note that compound 13 has some structural elements incommon with cis-3-methylfentanyl (14),^(21,22) a non-classical opioidligand selective for the mu opioid receptor. Accordingly, thepreparation of compound 13 and related structures remains an importantgoal.

REFERENCES

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SUMMARY OF THE INVENTION

[0038] It is an object of the present invention to provide novelcompounds which bind to opioid receptors.

[0039] It is another object of the present invention to provide novelcompounds which are opioid receptors antagonists that bind with highaffinity.

[0040] It is another object of the present invention to provide novelopiates that are selective for the kappa receptor as compared to thedelta and mu receptors.

[0041] It is another object of the present invention to provide novelopiates that are selective for the mu and kappa receptors as compared tothe delta receptor.

[0042] It is another object of the present invention to provide novelopiates that are selective for the delta receptor as compared to the muand kappa receptors.

[0043] It is another object of the present invention to provide novelopiates that are pure antagonists at the mu, delta and kappa receptors.

[0044] It is another object of the present invention to provide methodsof making the novel compounds.

[0045] It is another object of the present invention to provide methodsof treating a variety of disease states with the novel opiate compoundsof the present invention.

[0046] The objects of the present invention may be accomplished withcompounds represented by formula (I), or pharmaceutically acceptablesalts thereof:

[0047] where

[0048] R₁ is hydrogen, an alkyl group, an aryl group, or an aralkylgroup;

[0049] R₂ is hydrogen, an alkyl group, an aryl group, or an alkarylgroup; and

[0050] R₃ is

[0051] each X is, independently, halogen, —OH, —OR, an alkyl group, anaryl group, —NR, —NHR, —N(R)₂, —CF₃, —CN or —C(O)NH₂, —C(O)NHR, or—C(O)N(R)₂;

[0052] each R is, independently, an alkyl group, an aryl group or analkaryl group;

[0053] n is 0 or an integer from 1 to 5; and

[0054] R_(a) is hydrogen or an alkyl group.

[0055] The objects above may also be accomplished with compoundsrepresented by formula

[0056] (II): or pharmaceutically acceptable salts thereof,

[0057] where

[0058] R₁ is an alkyl group or aralkyl group; and

[0059] R₃, R₄, R₅, R₆ are each, independently, hydrogen, an alkyl group,—OH, —NK, —NHR, —N(R)₂, halogen, —OR, —CF₃, —CN, —NO₂, or —NHC(O)R;

[0060] each R is, independently, an alkyl group, an aryl group, or analkaryl group; and

[0061] R₇ is hydrogen or an alkyl group.

[0062] The objects of the present invention may be also accomplishedwith compounds represented by formula (III), or pharmaceuticallyacceptable salts thereof:

[0063] where

[0064] R₁ is an alkyl group or an aralkyl group;

[0065] R₂ is hydrogen, an alkyl group, an aralkyl group, ═O, —NH₂, —NHR,—N(R)₂, —NHC(O)R, —NRC(O)R, —NHC(O)R₅, or —NRC(O)R₅;

[0066] R₃ and R₄ may be hydrogen or methyl, with the proviso that whenPs is methyl then R, is hydrogen and when R₃ is hydrogen then R₄ ismethyl;

[0067] each R is, independently, an alkyl group, an aryl group, or analkaryl group; and

[0068] R₅ is

[0069] each X is, independently, halogen, —OH, —OR, an alkyl group, anaryl group, —NJ %, —NHR, —N(R)₂, —CF₃, —CN, —C(O)NH₂, —C(O)NHR, or—C(O)N(R)₂;

[0070] each R is, independently, an alkyl group, an aryl group, or analkaryl group;

[0071] n is 0 or an integer from 1 to 5; and

[0072] R_(a) is hydrogen or an alkyl group.

[0073] The objects above may be accomplished with compounds representedby formula (IV), or pharmaceutically acceptable salts thereof:

[0074] where

[0075] R_(a) and R_(b) are each, independently, hydrogen or an alkylgroup, or R_(a) and R_(b), together, form a cycloalkyl group;

[0076] each X is, independently, an alkyl group;

[0077] ◯ is a five- or six-membered aryl or heteroaryl group;

[0078] each Z is, independently, an alkyl group, —OH, —OR, halogen,—CF₃, —CN, —NH₂, —NHR, or —N(R)₂;

[0079] each R is, independently, an alkyl group, an aryl group, or analkaryl group;

[0080] each W is an alkyl group;

[0081] n is 0 or an integer from 1 to 4;

[0082] y is 0 or an integer from 1 to 5;

[0083] z is 0 an integer from 1 to 8; and

[0084] R₅ is an alkyl group, alkenyl group, or aralkyl group.

[0085] A more complete appreciation of the invention and many of theattendant advantages thereof will be readily obtained as the samebecomes better understood by reference to the following detaileddescription when considered in connection with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0086]FIG. 1: Synthesis of compounds represented by formula (II).

[0087]FIG. 2: Synthesis of compounds represented by formula (III). (A)synthesis of compounds in which R₃ is methyl (9β-compounds). (B)synthesis of compounds in which R₄ is methyl (4β-compounds).

[0088]FIG. 3: Retrosynthetic analysis for the synthesis of compoundsrepresented by formula (IV).

[0089]FIG. 4: Synthesis of compounds represented by formula (IV).

[0090]FIG. 5: Synthesis of compounds (7) as described in Example 1.

[0091]FIG. 6: Data from screening of library described in Example 1 at100 nM against the kappa-selective ligand [³H]U69,593 (percentinhibition).

[0092]FIG. 7: Comparison of ratios of radioligand binding and GTPγSassays for compound 8, naltrexone, nor-BNI, 5d, and 5a-c described inExample 1, the N-trans-cinnamyl derivatives of 4b. The radioligand andGTPγS binding data for 5a-d were taken from ref. 9 cited in Example 1.

[0093]FIG. 8: Synthesis of compounds (7) and (8) as described in Example2.

[0094]FIG. 9: Structural representation of (a) Naltrexone, (b)3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, and (c)8a-methyl-4a-(3-hydroxyphenyl)-octahydrobenzo[e]isoquinoline (Example2).

[0095]FIG. 10: Structure of(±)-[2-phenethyl-8a-methyl-4a-(3-hydroxymethyl)]octahydrobenzo[e]isoquinoline(8) HCl described in Example 2 by single crystal X-ray analysis.

[0096]FIG. 11: Synthesis of compound (18) as described in Example 3.

[0097]FIG. 12: Synthesis of compound (21) as described in Example 3.

[0098]FIG. 13: Synthesis of compound (5c) as described in Example 4.

[0099]FIG. 14: X-Ray structure of (5b) described in Example 4 drawnusing the experimentally determined coordinates.

[0100]FIG. 15: Conformational representation of naltrexone (1b),N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, and2-alkyl-9β-5-(3-hydroxyphenyl)morphan. These compounds are described inExample 4.

[0101]FIG. 16: Synthesis of compound (17) as described in Example 5.

[0102]FIG. 17: Synthesis of compound (3) as described in Example 6.

[0103]FIG. 18: Synthesis of 4β-5-phenylmorphans as described in Example7.

DETAILED DESCRIPTION OF THE INVENTION

[0104] The present invention relates to a group of compounds thatcontain a piperidinyl, or a bridged piperidinyl group. The inventivecompounds have been found to have a variety of different activities whenbound to opioid receptors.

[0105] Compounds of Formula (I)

[0106] In formula (I), R₁ is hydrogen, an alkyl group or an aralkylgroup. As used throughout this disclosure, the terms “alkyl group” or“alkyl radical” encompass all structural isomers thereof, such aslinear, branched and cyclic alkyl groups and moieties. Unless statedotherwise, all alkyl groups described herein may have 1 to 8 carbonatoms, inclusive of all specific values and subranges therebetween, suchas 2, 3, 4, 5, 6, or 7 carbon atoms. As used herein, the term “aralkylgroup” refers to an aryl moiety bonded to an alkyl radical. The arylmoiety may have 6 to 20 carbon atoms. The aryl moiety may contain onlycarbon and hydrogen atoms. Alternatively, the aryl moiety may containheteroatoms, for example 1, 2, or 3 heteroatoms (e.g., oxygen, nitrogen,and sulfur). A particularly preferred aryl moiety is phenyl-. The alkylradical of the aralkyl group may as described above when K is an alkylgroup. The alkyl group or moiety and/or the aryl moiety may besubstituted. Suitable substituents include halogens (F, Cl, Br and I),alkyl groups (e.g., C₁-C₈), alkoxy groups (e.g., C₁-C₈ alkoxy groups),—CF₃, —CN, —NH₂, —NHR, or —N(R)₂. The R groups are, independently, analkyl group (such as described for R₁ in formula (I) above), an arylgroup (such as phenyl) or an aralkyl group group (such as benzyl). Ingroups in compounds of formula (I)-(IV) where two R groups are bonded tothe same atom, i.e., —N(R)₂, the R groups may, together, form a cyclicalkyl group. Such a cyclic alkyl group may, preferably, contain 2 to 8carbon atoms, with 4 or 5 carbon atoms particularly preferred.

[0107] Preferably, R₁ is unsubstituted. In a preferred embodiment, R₁ isa C₁-C₈ alkyl group or a C₆-C₁₀aryl-C₁-C₈-alkyl group. In a morepreferred embodiment, R₁ is a C₁-C₄ alkyl group or a phenyl-C₁-C₄-alkylgroup. Even more preferably, R₁ is a C₁-C₃ alkyl group or aphenyl-C₁-C₃-alkyl group. Most preferably, R₁ is a methyl group, anisopropyl group, or a phenethyl group.

[0108] R₂ in formula (I) may be hydrogen, an alkyl group, an aryl groupor an alkaryl group. Suitable alkyl and alkaryl groups are as describedfor R₁ above. The aryl group may be as described for the aryl moiety ofR₁ above. Preferably, R₂ is hydrogen.

[0109] R₃ in formula (I) is one of the following groups:

[0110] In these groups, the phenyl ring may be unsubstituted (n is 0) orsubstituted with 1, 2, 3, 4, or 5 X groups, each X is, independently,halogen (e.g., chlorine or fluorine), —OH, —OR, an alkyl group (such asdescribed for R₁ in formula (I) above), an aryl group (such as phenyl),—NH₂, —NHR, —N(R)₂, —CF₃, —CN, —C(O)NH₂, —C(O)NHR, or —C(O)N(R)₂. The Rgroups are, independently, an alkyl group (such as described for R₁ informula (I) above), an aryl group (such as phenyl) or an aralkyl groupgroup (such as benzyl). Preferred X groups are chlorine, fluorine, —OH,—OCH₃ and —NH₂. Preferably, n is 1. The X group(s) may be located at theortho, meta and para positions. The para position is preferred,especially when X is —OH.

[0111] R^(a) in the formulas above may be hydrogen or an alkyl group.Suitable alkyls are as described for R₁ in formula (I) above.Preferably, R_(a) is hydrogen or methyl.

[0112] The absolute configuration of the carbon atom to which R₁ isbonded may be (R) or (S). The (S) configuration is preferred.

[0113] The compounds of formula (I) are preferably opiates withpreferential affinity for the μ/κ opioid receptors and comparably lessaffinity for δ receptors. In a preferred embodiment, these compounds arepure antagonists. The ratio of affinity for the δ receptor to the κreceptor (δ/κ) may be at least 1.5, preferably at least 2.0, morepreferably at least 20, still more preferably at least 100, even stillmore preferably at least 750 and most preferably at least 800. The μ/κratio may be 0.002 to 500.

[0114] The compounds of formula (I) may be prepared using well-knownsynthetic techniques by condensing an acid of the formula R₃—CO₂H withan amine represented by the formula:

[0115] The acid is preferably converted into an activated ester in orderto couple with the amine. A BOP ester is preferred. In a particularlypreferred embodiment, a variety of compounds within the scope of formula(I) may be simultaneously synthesized and evaluated usingwell-established combinatorial synthesis techniques, for example, asdescribed in Example 1.

[0116] Compounds of Formula (II)

[0117] In formula (II), R₁ is an alkyl group or an aralkyl group. Thesegroups may be as defined for R₁ in formula (I). In a preferredembodiment, R₁ is a C₁-C₈ alkyl group or a C₆-C₁₀ aryl-C₁-C₈-alkylgroup. In a more preferred embodiment, R₁ is a C₁-C₄ alkyl group or aphenyl-C₁-C₄-alkyl group. Even more preferably, R₁ is a C₁-C₂ alkylgroup or a phenyl-C₁-C₃-alkyl group. Most preferably, R₁ is a methylgroup or a phenethyl group.

[0118] R₇ is hydrogen or an alkyl group, preferably an alkyl group.Suitable alkyl groups are as described above for R₁. Preferably, R₇ ismethyl.

[0119] The substituents R₃, R₄, R₅ and R₆ on the fused aromatic ring maybe, independently, hydrogen, an alkyl group, —OH, —NH₂, —NHR, —N(R)₂,halogen (e.g., fluorine and chlorine), —OR, —CF₃, —CN, —NO₂, or—NHC(O)R. The R groups are, independently, an alkyl group (such asdescribed for R₁ in formula (I) above), an aryl group (such as phenyl)or an aralkyl group group (such as benzyl). Methyl and ethyl are themore preferred alkyl groups, and methyl is most preferred. Methoxy is apreferred —OR group. In one embodiment, R₃, R₄, R₅ and R₆ are eachhydrogen. In another embodiment, at most three of R₃, R₄, R₅ and R₆ areother than hydrogen. In another embodiment, at most two of R₃, R₄, R₅and R₆ are other than hydrogen. In yet another embodiment, only one ofR₃, R₄, R₅ and R₆ is other than hydrogen. In an embodiment where thefused aromatic ring contains alkyl groups, one, two or three of R₃, R₄,R₅ and R₆ are alkyl groups.

[0120] The stereochemical relationship between R₇ and the hydroxyphenylgroup may be cis or trans. The cis stereochemistry is preferred. Alloptical isomers of these compounds are within the scope of the presentinvention.

[0121] The compounds of formula (II) are opiates which are preferablypure opioid receptor antagonists. In a particularly preferredembodiment, the opiates are selective for the mu and/or kappa receptoras compared to delta receptors. The δ/κ selectivity may be, at least2:1, but is preferably higher, such as at least 5:1, 10:1, 20:1, 25:1,30:1, or 50:1. The δ/μ selectivity may be at least 2:1, but ispreferably higher, such as at least 5:1, 10:1, 15:1, 20:1, 25:1, 30:1,or 50:1

[0122] The compounds of formula (II) may be prepared, for example, asshown FIG. 1. These compounds may also be prepared as described inExamples 2 and 3 with appropriate modification of the various R groups.

[0123] Compounds of Formula (III)

[0124] In formula (III), R₁ may be an alkyl group or an aralkyl group.These groups may be as defined for R₁ in formula (I). In a preferredembodiment, R₁ is a C₁-C, alkyl group or a C₆-C₁₀ aryl-C₁-C₈-alkylgroup. In a more preferred embodiment, R₁ is a C₁-C₄ alkyl group or aphenyl-C₁-C₄-alkyl group. Even more preferably, R₁ is a C₁-C₂ alkylgroup or a phenyl-C₁-C₃-alkyl group. Most preferably, R₁ is larger thana methyl group, such as a phenethyl group.

[0125] R₂ in these compounds may be hydrogen, an alkyl group, an aralkylgroup, ═O, —NH₂, —NHR, —N(R)₂, —NHC(O)R, —NRC(O)R, —NHC(O)R₅, or—NRC(O)R₅. The alkyl or aralkyl group may be as described for R₁ informula (I). The R groups are, independently, an alkyl group (such asdescribed for R₁ in formula (I) above), an aryl group (such as phenyl)or an aralkyl group group (such as benzyl). The R₅ group of formula(III) has the same structure for R₃ in formula (I) discussed above. Allof the embodiments described for R₃ in formula (I) apply to R₅ informulla (HI). Preferably, R₂ is hydrogen, an alkyl group, or an amidogroup, i.e., —NHC(O)R₅, or —NRC(O)R₅. More preferably, R₂ is hydrogen oran amido group.

[0126] R₃ and R₄ may be hydrogen or methyl. However, when R₃ is methylthen R₄ is hydrogen and when R₃ is hydrogen then R₄ is methyl.

[0127] The compounds of formula (III) are preferably opiates which areopioid receptor pure antagonists. When R₂ is hydrogen, these compoundshave a preferential affinity for the μ receptors, as compared to κ or δreceptors. In this embodiment, the μ/δ selectivity may be at least 2:1,but is preferably higher, e.g., at least 5:1, 10:1, 25:1, 50:1, 100:,150:1 or 200:1. In this embodiment, the μ/κ selectivity may be at least2:1, 5:1, 10:1 or 25:1. When R₂ is an amido group, the δ/μ selectivitymay be at least 2:1, but is preferably higher, e.g., at least 5:1, 10:1,25:1 or 50:1.

[0128] The compounds of formula (III) may be synthesized, for example,as shown in FIG. 2. The synthesis of compounds in which R₃ is methyl(9β-compounds) is shown in FIG. 2A. Compounds in which R₄ is methyl(4β-compounds) may be synthesized as shown in FIG. 2B. For specificexamples of such preparations, see the following Examples 3-5 and 7.

[0129] Compounds of Formula (IV)

[0130] R_(a) and R_(b) are each, independently, hydrogen or an alkylgroup. The alkyl group may be as described for R₁ in formula (I).Preferably, R_(a) and R_(b) are ethyl. Alternatively, R_(a) and R_(b),together, form a cycloalkyl group. Suitable cycloalkyl groups includethose having 3 to 7 carbon atoms. Cycloalkyl groups having four or fivecarbon atoms are especially preferred.

[0131] Each X, if present, may be an alkyl group. Suitable alkyl groupsare as described for R₁ in formula (I) above. The number of X groups,determined by the variable n, may be 0, 1, 2, 3 or 4. Preferably, n is0.

[0132] The group ◯ is a five- or six-membered aryl or heteroaryl group.Phenyl is the preferred aryl group. Suitable heteroaryl groups may haveone, two, three or four heteroatoms, e.g., nitrogen, oxygen or sulfur.Specific examples of heteroaryl groups include pyridine, pyridazine,pyrimidine, pyrazine, traiazine (e.g., 1,2,3-; 1,2,4-; 1,3,5-),1,2,4,5-tetrazine, furan, thiophene, oxazole, isothiazole, thiadazole,pyrazole, pyrrole, and imidazole.

[0133] Preferably, ◯ is a phenyl group. These compounds are representedby the formula:

[0134] Each Z, if present, is, independently, an alkyl group, —OH, —OR,halogen, —CF₃, —CN, —NH₂, —NHR, or —N(R)₂. The R groups are,independently, an alkyl group (such as described for R₁ in formula (I)above), an aryl group (such as phenyl) or an aralkyl group group (suchas benzyl) Suitable alkyl groups are as described for R₁ in formula (I)above. The number of Z groups, determined by the variable y, may be 0,1, 2, 3, 4, or 5. Preferably, y is 1 or 0. More preferably, y is 0.

[0135] Each W, if present, is an alkyl group. Suitable alkyl groups areas described for R₁ in formula (I) above. Preferably, W is a methyl. Thenumber of alkyl groups on the piperdine ring is determined by z. Thevariable z may be 0 or an integer from 1 to 8, inclusive of 2, 3, 4, 5,6, or 7. Preferably, z is 1, 2, or 3. In a preferred embodiment, atleast one W group is bonded to a carbon atom adjacent to the carbon atombearing the diamino substituent. The stereochemical relationship betweenthis W group and the diamino substituent may be cis or trans. Whenmultiple W groups are present on the piperdine ring, the stereochemicalrelationship between W the groups may be cis or trans.

[0136] In formula (IV), R₅ is an alkyl group, an alkenyl group, or anaralkyl group. The alkyl group and/or the aralkyl group may be asdefined for R₁ in formula (I). Preferably, these groups have 1 to 8carbon atoms, more preferably 1 to 5 carbon atoms. The alkenyl group mayhave up to three double bonds, more preferably, up to two double bonds,and, most preferably, one double bond. An alkenyl group is preferred.Most preferably, R₅ is an allyl group.

[0137] The compounds formula (IV) are opiates which are preferablyagonists that are selective for the delta receptor. The δ/μ selectivitymay be at least 2:1, but is preferably higher, e.g., at least 5:1, 10:1,25:1, 50:1, 100:1 or 200:1. The δ/κ selectivity may be at least 2:1, butis preferably higher, e.g., at least 5:1, 10:1, 25:1, 50:1, 100:1,200:1, 250:1 or 500:1.

[0138] The compounds of formula (IV) may be synthesized, for example, inaccordance with the retrosynthetic analysis shown in FIG. 3. An exampleof a reaction sequence to obtain compounds of formula (IV) is shown inFIG. 4. For specific examples of syntheses of compounds of formula (IV),see the Example 6 below.

[0139] Compounds (I)-(IV) may be in the form of a pharmaceuticallyacceptable salt via protonation of the amine with a suitable acid. Theacid may be an inorganic acid or an organic acid. Suitable acidsinclude, for example, hydrochloric, hydroiodic, hydrobromic, sulfuric,phosphoric, citric, acetic and formic acids.

[0140] The receptor selectivities discussed above are determined basedon the binding affinities at the receptors indicated.

[0141] The compounds of the present invention may be used to bind opioidreceptors. Such binding may be accomplished by contacting the receptorwith an effective amount of the inventive compound. Of course, suchcontacting is preferably conducted in a aqueous medium, preferably atphysiologically relevant ionic strength, pH, etc.

[0142] The inventive compounds may also be used to treat patients havingdisease states which are ameliorated by binding opioid receptors. Suchdiseases states include heroin addiction, pain, i.e., the compounds areused as analgesics. The compounds of the inventive may also be used toreverse mu-induced respiratory depression, as cytostatica agents, asantimigraine agents, as immunomodulators, as immunosuppressives, asantiarthritic agents, as antiallergic agents, as virucides, to treatdiarrhea, as antidepressants, as uropathic agents, as antitussives, asantiadditive agents, as anti-smoking agents, to treat alcoholism, ashypotensive agents, or to treat obesity.

[0143] The compounds may be administered in an effective amount by anyof the conventional techniques well-established in the medical field.For example, the compounds may be administered orally, intraveneously,or intramuscularly. When so administered, the inventive compounds may becombined with any of the well-known pharmaceutical carriers andadditives that are customarily used in such pharmaceutical compositions.For a discussion of dosing forms, carriers, additives, pharmacodynamics,etc., see Kirk-Othmer Encyclopedia of Chemical Technology, FourthEdition, Vol. 18, 1996, pp. 480-590, incorporated herein by reference.The patient is preferably a mammal, with human patients especiallypreferred.

[0144] Having generally described this invention, a furtherunderstanding can be obtained by reference to certain specific exampleswhich are provided herein for purposes of illustration only and are notintended to be limiting unless otherwise specified. In each of theExamples, the numbering of compounds and references cited are specificto each Example.

EXAMPLES Example 1 Identification of Opiates Selective for the OpioidReceptors

[0145] Summary

[0146] A three-component library of compounds was prepared in parallelusing multiple simultaneous solution phase synthetic methodology. Thecompounds incorporated a(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine group as one of themonomers. The other two monomers, which included N-substituted orunsubstituted Boc protected amino acids and a range of substituted arylcarboxylic acids, were selected to add chemical diversity. Screening ofthese compounds in competitive binding experiments with the kappa opioidreceptor selective ligand [³H]U69,593 led to the identification of a κopioid receptor selective ligand,N-{(2′S)-[3-(4-hydroxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(8, RTI-5989-29). Additional SAR studies suggested that 8 possesseslipophilic and hydrogen bonding sites that are important to its opioidreceptor potency and selectivity. These sites appear to existpredominantly within the kappa receptor since the selectivity arisesfrom a 530-fold loss of affinity of 8 for the mu receptor and an 18-foldincrease in affinity for the kappa receptor relative to the mu-selectiveligand,(+)-N-[trans-4-phenyl-2-butenyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(5a). This degree of selectivity observed in the radioligand bindingexperiments was not observed in the functional assay. According to itsability to inhibit agonist stimulated binding of [³⁵S]GTPγS at all threeopioid receptors, compound 8 behaves as a mu/kappa opioid receptor pureantagonist with negligible affinity for the delta receptor.

[0147] Chemistry

[0148] Coupling of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(4b) (FIG. 5) with an appropriate tert-butoxycarbonyl-protected aminoacid (Boc-protected) followed by removal of the Boc-protecting groupwith trifuoroacetic acid (TFA) in methylene chloride followed byreduction using a tetrahydrofuran (THF) solution of borane-dimethylsulfide complex gave the intermediate amines (6a-k) in 15-78% yields(FIG. 5). These intermediates 6 were subjected to column chromatographyor crystallization as necessary to obtain pure compounds. The finalproducts (7) were prepared in scintillation vials via amide bondformation by coupling with a wide variety of commercially availablecarboxylic acids. A representative list of such carboxylic acids followsthe Experimental section of this Example.Benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphoniumhexafluorophosphate (BOP reagent) in THF was employed as the couplingreagent which provided very clean products after aqueous work-up. Thesecompounds were used directly in screening without additionalpurification. Pure compounds for further SAR analysis were obtained bypurification of library samples or by single compound synthesis byconventional synthetic methodology and characterized by MS, ¹H NMR, andelemental analyses.

[0149] Results and Discussion

[0150] The results from the screening of the 288-compound library incompetitive binding against the kappa opioid receptor selective ligand[³H]U69,593 are illustrated graphically in FIG. 6. Several compoundsshowed significant inhibition of radioligand binding at 100 nM with 8(plate 4, well 20, 71%) being the best (FIG. 6). The data for %inhibition of [³H]U69,593 binding by selected library compounds 8-23 at100 nM are listed in Table 1.

[0151] A comparative analysis of the structures related to compounds9-23, which have less binding affinity relative to 8, readilyillustrates the importance for kappa receptor binding of each structuralsubunit of group R₃ (Table 1). Compound 9, a diastereomer of 8, wherethe carbon to which the R₁ isopropyl group is connected has the oppositestereochemistry, shows less binding affinity (11%) for the opioid kappareceptor. The sensitivity to orientation (R or S) at this stereogeniccenter suggests that the isopropyl group may be working in tandem withanother structural feature of the R₃ unit to both increase binding in 8and decrease binding in 9. The difference in affinity of compounds 8(71%) and 10 (28%) suggests that the 4-hydroxyl substituent in 8 is moreeffective for high kappa binding affinity. Furthermore, the weakerinhibition displayed by compounds 11 (20%) and 12 (25%) possessing metaand ortho hydroxyl substituents respectively, pinpoints the paraplacement of the para-hydroxyl group as the optimum position. The factthat compound 19, which lacks the isopropyl group but has thepara-hydroxyphenylpropionic substituent, shows less affinity (11% vs.71%) relative to 8, adds additional support to the importance of the R₁isopropyl and 4-hydroxyphenyl groups to the kappa-selective binding. Thelow affinity of compound 20 (20%) which has a methyl substituent inposition (R₁) shows that a methyl group may be less effective than theisopropyl group. This strengthens the notion that both the isopropylgroup (R₁) and the 4-hydroxyphenyl group for R₃ are working together toelicit high affinity binding at the kappa opioid receptor in compound 8.The results for compound 13 (6%) suggests that two methylene groups aremore effective between the phenyl ring and the amide carbonyl indiversity element R₃, presumably because the para-hydroxyl group cannotreach its site of interaction in the truncated derivative. Furthermore,the lower inhibition of binding for compound 14 (15%) which incorporatesa trans double bond in the connecting chain shows that the length of thechain is not optimal to impart high binding affinity, implying thatflexibility is also preferred in this carbon chain to provide properligand and receptor alignment. The lower affinity of the 4-fluoroderivative 15 (26%) and the 4-methoxy derivative 18 (16%) supports thesuggestion that a hydrogen bond exists between ligand 8 and the receptorwith compound 8 donating the hydrogen. This is further supported by thelower affinity of the 3,4-dihydroxyl derivative 16 (31%) which canhydrogen bond internally and the 3-methoxy-4-hydroxy derivative 17 (42%)whose hydrogen bond could be sterically encumbered by interference froman adjacent methoxy group. Interestingly, all compounds having methyland not hydrogen as the second diversity element R₂, 21 (0%), 22 (1%),and 23 (7%) displayed very low binding affinity usually at baseline(DMSO blank) levels. Apparently, position R₂ is preferablyunsubstituted. These results suggest that the amide group may be part ofa separate hydrogen-bonding interaction to place the key R₁ isopropyland R₃ p-hydroxyphenyl rings in their correct positions for stronginteraction with the receptor. Alternatively, the N-methyl substituentmay be decrease ligand affinity through repulsive steric interactions.

[0152] Taken together, the data suggests that the high binding affinitydisplayed by 8 results from a combination of several structural featurespresent in its N-substituent. These include a 4-hydroxyl group in thependant phenyl ring of group R₃, the length and flexibility of thecarbon chain connecting this ring to the amide carbonyl and the presenceof a beta (position R₁) isopropyl group with an S configuration at theadjacent stereogenic center. The data analysis suggests that theprinciple stabilizing interactions could be related to binding of thehydroxyl and isopropyl substituents with the other atoms of theN-substituent substructure acting to hold these two binding elements inoptimum overlapping positions within the receptor site. Alternatively,the isopropyl group could be acting to bias the conformation of moleculeto provide the best alignment of the 4-hydroxyphenylpropionic acidside-chain with its binding site.

[0153] In order to gain additional SAR information, a pure sample of 8along with compounds 24-27 which vary at the R₁ position alone wasprepared for study. Table 2 lists the K_(i) values for these derivativesat the mu and kappa opioid receptors along with the K_(i) values for themu-selective reference compound 5a, naltrexone, and the kappa-selectiveantagonist nor-BNI. The delta receptor assay was not performed forcompounds 24-27 as all previous derivatives of 8 had shown no affinityfor this receptor subtype. This study revealed that 8 not only activelybinds the kappa receptor (K_(i)=6.9 nM) but also possessed a 57-foldselectivity for the kappa vs. the mu receptor (K_(i)=393 nM)and >870-fold selectivity for the kappa vs. the delta receptor(K_(i)>5700 nM). Compound 8 thus displays a high degree of opioid kappareceptor subtype selectivity.^(1,2) Nor-BNI (1) has a higher affinityfor the kappa receptor than 8 and has a greater kappa selectivityrelative to the mu receptor. However, 8 is more selective for the kappareceptor relative to the delta receptor. A part of these differencescould be due to the use of different tissues and radioligands.

[0154] The data for the beta isobutyl substituent compound 24, whichresults formally from insertion of a methylene between the isopropylgroup and its adjacent stereogenic center of compound 8, displays a lossof affinity for the kappa receptor while maintaining the same affinityfor the mu receptor as compound 8. The net effect is a loss ofselectivity between the mu and kappa receptor subtypes. Compound 26(R₁=cyclohexyl) shows a similar loss of affinity for the kappa receptorwith a gain in affinity for the mu receptor resulting in a similar lossof selectivity. Compound 25 with an R₁ sec-butyl group shows a slightdecrease in both kappa and mu potency but retains selectivity, thoughits magnitude is lower relative to 8. Compound 27 (R₁=benzyl) displayeda binding profile completely different from that seen in 8 with atremendous increase in mu potency and concomitant loss of kappa potency.This was not unexpected since compound 27, prepared from the amino acidphenylalanine, possesses an N-substituent with a phenyl ring separatedfrom the piperidine ring by three methylene groups which are known tofavor mu binding.^(1,2) It was for this reason that phenylalanine wasexcluded from use in the library synthesis. Overall, the behaviors ofthe various R₁ derivatives of 8 indicate that the size of the lipophilicgroup in position R₁ is important to both the potency and receptorsubtype selectivity of the ligand. Furthermore, the data supports thehypothesis that the isopropyl group in 8 is not simply biasing theconformation of side-chain but is instead interacting with the receptordirectly in a ligand stabilizing interaction.

[0155] The agonist/antagonist activity of compound 8 was measured bydetermining its ability to either stimulate or reverse opioid agoniststimulated binding of the nonhydrolyzable GTP analog, [³⁵S]GTPγS, in allthree opioid receptor assays (Table 3).³ Table 3 includes data obtainedfor naltrexone, the standard nonselective opioid pure antagonist,nor-BNI, the prototypical kappa-selective antagonist, and the potent,mu-favoring opioid antagonist (5a). The kappa selectivity displayed bycompound 8 in the inhibition of radioligand binding assay was notobserved in the [³⁵S]GTPγS functional assay. This is not an a typicalsituation; radioligand binding results often differ substantially fromthose seen in functional assays but this typically involves agonists.The antagonists, naltrexone, normally display K_(i) (radioligand)/K_(i)(GTPγS) binding ratios near unity whereas ratios greater than unity havebeen observed for antagonists of the N-substitutedtrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine series.¹ Thisphenomenon is illustrated graphically in FIG. 7. The trans-cinnamylderivatives 5a-c and compound 5d display K_(i) (radioligand)/K_(i)(GTPγS) binding ratios greater than unity in the mu and kappa receptorassays which is distinctly different from the response demonstrated bynaltrexone. In the present case compound 8 is found to behave likenaltrexone in the kappa receptor assays with a ratio near unity which isfar different from the behavior seen for 5a-c and 5d, which show ratiosof 118, 228, 63, and 85, respectively. In the mu receptor assay on theother hand, compound 8 with a ratio of 54 behaves like 5a-c and 5d whichgive ratios of 19, 66, 43, and 15. This differential response of 8 inthe [³⁵S]GTPγS assay is sufficiently large so as to erode the kappareceptor selectivity observed for 8 in the radioligand binding assays.Note that the K_(i) (radioligand)/K_(i) (GTP) binding ratios for nor-BNIat the mu and kappa receptor are 2.8 and 7.36, respectively.

[0156] Conclusions

[0157] The identification of compound 8, which displays a highlyselective kappa vs. mu receptor inhibition of radioligand bindingprofile and a potent mu/kappa opioid antagonist profile, demonstratesthe effectiveness of the biased library approach to lead compoundgeneration. Since both the mu and kappa receptors may be important inheroin abuse, compound 8 should be useful as a treatment medication forheroin abuse.

[0158] Experimental Section

[0159] Melting points were determined on a Thomas-Hoover capillary tubeapparatus and are not corrected. Elemental analyses were obtained byAtlantic Microlabs, Inc. and are within ±0.4% of the calculated values.All optical rotations were determined at the sodium D line using aRudolph Research Autopol III polarimeter (1-dm cell). ¹H NMR spectrawere determined on a Bruker WM-250 spectrometer using tetramethylsilaneas an internal standard. Silica gel 60 (230400 mesh) was used for allcolumn chromatography. Mass spectral data was obtained using a FinneganLCQ electrospray mass spectrometer in positive ion mode at atmosphericpressure. All reactions were followed by thin-layer chromatography usingWhatman silica gel 60 TLC plates and were visualized by UV, charringusing 5% phosphomolybdic acid in ethanol and/or exposure to iodinevapor. All solvents were reagent grade. Tetrahydrofuran and diethylether were dried over sodium benzophenone ketyl and distilled prior touse. Methylene chloride was distilled from calcium hydride prior to use.

[0160] General Method for the Introduction of Diversity Elements R₁ andR₂ into Structure 6. (+)-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine(4b) (11.5 mmol), the appropriate Boc-protected amino acid (11.5 mmol)and BOP reagent (11.5 mmol) were combined in THF (150 mL) at roomtemperature, and to this was immediately added triethylamine (TEA) ordiisopropylethylamine (25.3 mmol). After stirring for 1 h, the reactionmixture was poured into ethyl ether (500 mL) and water (150 mL) in aseparatory funnel. The mixture was shaken and the aqueous layer removed.This procedure was repeated using 150 mL saturated NaHCO₃ and 150 mLbrine. The organic layer was diluted with hexane until cloudy and dried(Na₂SO₄), concentrated under reduced pressure, then dissolved in 100 mLchloroform (stored over K₂CO₃), and concentrated again. This was placedon a high vacuum system to remove residual solvent yielding a foamyyellow/white solid.

[0161] After remaining under vacuum on the pump overnight, thisunpurified material was dissolved in methylene chloride 45 mL and cooledto −20° C. (methanol/ice). To this was added neat trifluoroacetic acidin 10-mL portions over 2 min to give a total addition of 30 mL. Theentire mixture was stirred for exactly 30 min and then the cooling bathwas removed for exactly 30 min. At this point, the reaction mixture waspoured into a 1 L beaker containing a large stir bar and a rapidlyagitated mixture of saturated bicarbonate solution (400 mL) andchloroform (150 mL). After completed addition, the pH of the mixture wasverified to be 10 and adjusted with solid sodium bicarbonate ifnecessary. This mixture was poured into a separatory funnel. Anyprecipitated organic compounds were rinsed into the separatory funnelusing a small amount of methanol. The beaker was then rinsed with asmall amount of water which was added to the separatory funnel. Thelayers were agitated, separated, and the aqueous layer extracted fiveadditional times using 3:1 methylene chloride:THF. It was observed thatcompounds with small groups R₁ required additional extractions and/orsodium chloride saturation of the aqueous layer. The combined organiclayers were dried over sodium sulfate and the solvent removed at reducedpressure. The material was then placed on a high vacuum pump to yield ayellow foamy solid.

[0162] Unpurified material from the deprotection step was dissolved inTHF (150 mL) and cooled to −20° C. (methanol/ice). To this stirredmixture was added a solution of borane dimethylsulfide complex, 2M inTHF (110 mmol) dropwise. The solution was then heated to reflux and heldfor 3 h after which time, the solution was cooled to −20° C., and tothis was carefully added methanol (72 mL) dropwise. This mixture wasstirred for 1 h at room temperature, 16.4 mL of 1M HCl in ethyl etherwas added, the solution was allowed to stir for 30 min, and the solventsremoved on a rotary evaporator. The resulting residue was partitionedbetween 3:1 methylene chloride:tetrahydofuran and water, the pH wasadjusted to 10 with saturated sodium bicarbonate, and the aqueous layerwas saturated with sodium chloride and extracted several times with 3:1methylene chloride:tetrahydofuran. The combined organic layers weredried over sodium sulfate and the solvent removed. This material waspurified by flash chromatography on a silica gel column which wasprepared by slurry packing with chloroform. The impure compounds wereloaded on the column as a chloroform solution. Elution proceeded withneat chloroform followed by 3% methanol up to 10% methanol in chloroformas needed to elute the desired compounds. Product fractions werecombined and the solvent was removed on a rotary evaporator. Thismaterial was dissolved in a minimum of hot ethyl acetate and allowed tocrystallize. Crystalline material was isolated by filtration followed bywashing with a small amount of ice-cold ethyl acetate and used directlyin the next step after drying overnight in a vacuum oven.

[0163] Introduction of Diversity Element R₃ into Structure 7. Theappropriate pure diamine 6, produced in the previous step (0.05 mmol×thenumber of derivatives being prepared), was dissolved in THF (2 mL×thenumber of derivatives being prepared) and to this was added TEA (0.1mmol x the number of derivatives being prepared). Then, into prelabeled,20-mL scintillation vials containing a stir bar was added one of thechosen carboxylic acids (0.05 mmol). To this was added the appropriatefraction of the diamine/TEA/THF mixture followed by 50 mL of a 1 Msolution of BOP reagent in dimethylformamide (DMF). The vial was thencapped with a telfon-lined lid and stirred for 1 h at room temperature.After this time, 4 mL of ethyl ether and 2 mL of water were added to thevial. After shaking and allowing the layers to settle, the aqueous layerwas withdrawn with a pipette. Next, 2 mL of saturated sodium bicarbonatesolution was added and the procedure repeated. This was followed by asimilar wash with saturated sodium chloride solution. Sodium sulfate wasadded to the vial, and after drying, the mixture was pipetted into apreweighed, prelabeled 20-mL scintillation vial via a 6-in Pasteurpipette containing a small cotton plug. Following this, 2 mL ofchloroform was added to the drying agent and the vial shaken after whichthe chloroform rinse was filtered as above. The collecting vials wereplaced under a nitrogen outlet and allowed to evaporate. Once thesolvent was removed, the vials were placed in a high vacuum desiccatorand allowed to remain overnight. The vials were reweighed, and the crudeyield determined by difference. Since pilot studies showed that theBOP-coupling reaction produced very clean samples, the products wereused without further purification, and the purity was taken to be 100%.

[0164] Prior to screening, all compounds were diluted to a concentrationof 10 mM in dimethylsulfoxide (DMSO). Dilution was accomplished bydetermining the mean mmol/vial for each batch of 20 reactions using anExcel 3.0 spreadsheet. Weights deviating from the mean by >±10% weregrouped into a second and third set above and below the mean. These werealso averaged within the same parameters. Any compounds not fallingwithin the above sets were diluted individually according to theirweight. This procedure permitted sample dilution to be accomplishedusing a minimum number of different volume deliveries of DMSO. Oncediluted to 10 mM, 1-mL samples from each vial were withdrawn and placedin rows A and E (one compound/well) of a 1 mL×96-well polypropylenemicrotiter plate. Serial dilution was then performed using Matrixmultichannel pipettors which provided a 1-mM solution in rows B and Fand a 0.1-mM solution in rows C and G. Once all of the compounds weretransferred to plates and diluted to the proper concentration, theplates were placed in the refrigerator prior to assay.

[0165] N-(2′-Aminoethyl)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6a). Prepared from N-(tert-butoxy)-glycine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 15% yield: ¹H NMR (MeOH-d4) δ 7.13-7.062 (t, 1H,J=8.1 Hz), 6.77-6.74 (m, 2H), 6.59-6.55 (m, 1H), 3.31-3.29 (m, 1H),2.83-2.70 (m, 3H), 2.5 (d, 2H, J=3.1 Hz), 2.46-2.27 (m, 3H), 2.00 (s,1H), 1.6 (d, 2H, J=3.1 Hz), 1.68 (d, 1H, J=13.7 Hz), 1.29 (s, 3H), 0.89(d, 3H, J=7.0 Hz); ¹³C NMR (MeOH-d4) δ 158.5, 152.9, 130.0, 117.9,113.9, 113.3, 61.6, 57.1, 51.5, 40.2, 39.5, 39.1, 32.0, 28.2, 16.7. MS(electrospray) M+1=249. Calculated=249.

[0166]N-(2′-Methylaminoethyl)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6b). Prepared from N-(tert-butoxy)-sarcosine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 32% yield: ¹H NMR (MeOH-d4) δ 7.9 (t, 1H, J=7.7Hz), 6.77 (d, 1H), 6.74 (s, 1H), 6.58 (d, 1H), 2.95-2.90 (m, 1H),2.87-2.82 (m, 2H), 2.66 (dd, 12.61-2.55 (m, 2H), 2.54 (s, 3H), 2.52 (td,1H), 2.37 (td, 1H), 2.03-2.00 (m, 1H), 1.69 (brd, 1H), 1.30 (s, 3H),0.89 (d, 3H, J=7.0 Hz); ¹³C NMR (MeOH-d4) δ 130.0, 118.0, 113.8, 113.3,57.4, 56.7, 51.1, 48.2, 40.2, 39.4, 35.0, 31.9, 28.1, 16.6. MS(electrospray) M+1=263. Calculated=263.

[0167]N-[(2′S)-Aminopropyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6c). Prepared from N-(tert-butoxy)-L-alanine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 56% yield: ¹H NMR (MeOH-d4) δ 7.11-7.08 (t, 1H,J=7.7), 6.78-6.76 (d, 1H), 6.74 (s, 1H), 6.59-6.57 (d, 1H), 2.953-2.902(m, 1H), 2.874-2.826 (m, 2H), 2.676-2.647 (dd, 1H), 2.618-2.559 (m, 2H),2.548 (s, 3H), 2.541-2.400 (td, 1H), 2.342-2.284 (td, 1H), 2.030-2.002(m, 1H), 1.613-1.587 (brd, 1H), 1.303 (s, 3H), 0.800-0.786 (d, 3H,J=7.0); ¹³C NMR (MeOH-d4) d 130.0, 118.0, 113.8, 113.3, 57.4, 56.7,51.1, 48.2, 40.2, 39.4, 35.0, 31.9, 28.1, 16.6. MS (electrospray)M+1=263. Calculated=263.

[0168]N-[(2′S)-(Methylamino)propyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6d). Prepared from N-(tert-butoxy)-N-methyl-L-alanine¹⁷ and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 33% yield: ¹H NMR (MeOH-d4) δ 7.18 (t, 1H, J=7.9Hz), 6.76 (d, 1H), 6.73 (s, 1H), 6.57 (d, 1H), 2.72-2.64 (m, 2H),2.61-2.47 (m, 3H), 2.36 (s, 3H), 2.34-2.20 (m, 3H), 2.00-1.99 (m, 1H),1.56 (dd, 1H), 1.29 (s, 3H), 1.03 (d, 3H, J=6.2 Hz), 0.65 (d, 3H, J=6.9Hz); ¹³C NMR (MeOH-d4) δ 158.4, 153.3, 130.1, 117.9, 113.7, 113.3, 65.1,56.0, 52.9, 52.9, 40.0, 39.5, 33.7, 31.9, 28.0, 17.3, 16.7. MS(electrospray) M+1=277. Calculated=277.

[0169]N-[(2′S)-Amino-3′-methylbutyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6e). Prepared from N-(tert-butoxy)-L-valine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 78% yield: ¹H NMR (MeOH-d4) δ 7.126-7.062 (t, 1H),6.769-6.735 (m, 2H), 6.603-6.558 (m, 1H), 2.657-2.179 (m, 8H), 2.000(brs, 1H), 1.583-1.502 (m, 2H), 1.294 (s, 3H), 0.978-0.912 (q, 6H),0.789-0.761 (d, 3H); ¹³C NMR (MeOH-d4) δ 158.5, 153.3, 130.1, 117.8,113.8, 113.3, 63.4, 55.8, 54.1, 53.3, 40.0, 39.5, 33.1, 31.9, 28.1,19.6, 19.2, 16.8. MS (electrospray) M+1=291. Calculated=291.

[0170]N-[(2′R)-Amino-3′-methylbutyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6f). Prepared from N-(tert-butoxy)-D-valine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 62% yield: ¹H NMR (MeOH-d4) δ 7.11-7.08 (t, 1H),6.78-6.76 (d, 1H), 6.74 (s, 1H), 6.59-6.57 (dd, 1H), 3.139-3.097 (m,1H), 2.953 (brs, 1H), 2.894-2.865 (dd, 1H), 2.546-2.500 (m, 2H),2.401-2.292 (m, 3H), 2.046-2.034 (brm, 1H), 1.894-1.827 (sext, 1H),1.62-1.30 (m, 1H), 1.311 (s, 3H), 1.042-1.006 (dd, 6H), 0.834-0.820 (d,3H); ¹³C NMR (MeOH-d4) δ 152.9, 130.1, 118.0, 113.8, 113.3, 59.8, 58.8,55.2, 50.0, 40.4, 39.4, 31.6, 31.1, 28.0, 18.8, 18.5, 16.5. MS(electrospray) M+1=291. Calculated=291.

[0171]N-[(2′S)-Amino-4′-methylpentyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6 g). Prepared from N-(tert-butoxy)-L-leucine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 56% yield: ¹H NMR (MeOH-d4) δ 7.09 (t, 1H, J=7.9Hz), 6.76 (d, 1H, J=7.9 Hz), 6.73 (s, 1H), 6.57 (dd, 1H, J=2.2, 7.9 Hz),3.03-2.97 (m, 1H), 2.73 (d, 1H, J=11.2 Hz), 2.64 (d, 1H, J=11.1 Hz),2.56 (td, 1H, J=2.5, 12.0 Hz), 2.48 (dd, 1H, J=2.7, 11.4 Hz), 2.33 (td,1H, J=4.5, 12.7 Hz), 2.25 (dd, 1H. J=3.6, 12.4 Hz), 2.19-2.15 (m, 1H),2.01-2.00 (m, 1H), 1.75 (sept, 1H, J=6.6 Hz), 1.56 (d, 1H. J=13.0 Hz),1.29 (s, 3H), 1.27-1.15 (m, 2H). 0.94-0.91 (m, 6H), 0.07 (d, 3H, J=7.0Hz); ¹³C NMR (MeOH-d4) δ 158.3, 153.3, 130.1, 117.9, 113.7, 113.2, 65.7,56.0, 53.1, 46.5, 45.2, 40.0, 39.5, 31.9, 28.0, 25.8, 23.7, 22.6, 16.7.MS (electrospray) M+1=305. Calculated=305.

[0172]N-[(2′S)-Amino-3′-methylpentyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6 h). Prepared from N-(tert-butoxy)-L-isoleucine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 47% yield: ¹H NMR (MeOH-d4) δ 7.19 (t, 1H, J=7.9Hz), 6.76 (d, 1H, J=8.1 Hz), 6.73-6.73 (m, 1H), 6.58-6.56 (dd, 1H,J=2.1, 7.9 Hz), 2.86-2.82 (m, 1H), 2.75-2.73 (m, 1H), 2.65-2.57 (m, 2H),2.502-2.474 (dd, 1H, J=2.8, 11.4 Hz), 2.40-2.23 (m, 3H), 2.02-2.00 (m,1H), 1.59-1.50 (m, 2H), 1.46-1.41 (m, 1H), 1.30 (s, 3H), 1.24-1.17 (m,1H), 0.98-0.87(m, 6H), 300.78 (d, 3H, J=7.0 Hz); ¹³C NMR (MeOH-d4) δ158.3, 153.2, 130.1, 117.9, 113.7, 113.3, 61.9, 55.9, 53.1, 52.9, 49.0,40.0, 39.5, 39.3, 31.9, 28.0, 26.6, 16.7, 15.1, 11.8. MS (electrospray)M+1=305. Calculated=305.

[0173]N-[(2′S)-Amino-2′-cyclohexylethyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6i). Prepared from N-(tert-butoxy)-L-cyclohexylglycine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 63% yield: ¹H NMR (MeOH-d4) δ 7.18 (t, 1H. J=7.9),6.76 (d, 1H, J=7.8 Hz), 6.75 (s, 1H), 6.57 (d, 1H, J=7.8 Hz), 2.74-2.70(m, 2H), 2.63-2.55 (m, 2H), 2.47-2.45 (d, 1H, J=10.0 Hz), 2.48 (dd, 1H,J=2.9, 12.4 Hz), 2.36 (td, 1H, J=4.3, 12.6 Hz), 2.23 (t, 1H, J=11.6 Hz),2.00 (m, 1H), 1.76-1.74 (m, 3H), 1.67 (d, 2H, J=11.9 Hz), 1.57 (d, 1H.J=13.0 Hz), 1.39-1.16 (m, 7H), 1.09 (quint, 2H, J=12.4 Hz), 0.77 (d, 3H,J=6.8 Hz); ¹³C NMR (MeOH-d4) δ 158.3, 153.3, 130.1, 117.9, 113.7, 113.3,162.6, 55.8, 53.4, 53.1, 42.9, 40.0, 39.5, 31.9, 30.9, 30.5, 30.2, 28.0,27.6, 27.4, 16.7. MS (electrospray) M+1=331. Calculated=331.

[0174]N-[(2′S)-Methylamino-2′-phenylethyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)-piperidine(6j). Prepared from N-(tert-butoxy)-N-methyl-phenylglycine¹⁷ and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 44% yield: ¹H NMR (MeOH-d4) δ 7.34-7.22 (m, 5H),7.13 (t, 1H, J=8.2 Hz), 6.80-6.77 (m, 2H), 6.61-6.69 (m, 1H), 3.63 (dd,1H, J=3.7, 12.6 Hz), 2.73 (brd, 2H, J=7.6 Hz), 2.64-2.52 (m, 3H), 2.38(dd, 2H, J=3.6, 12.6 Hz), 2.25 (s, 3H), 2.04 (brd, 1H, J=6.3 Hz), 1.59(d, 1H, J=12.9), 1.312 (s, 3H), 0.818-0.790 (d, 3H, J=6.9); ¹³C NMR(MeOH-d4) δ 147.3, 142.5, 131.5, 119.5, 119.0, 118.0, 107.4, 103.2,102.7, 68.7, 68.233, 67.7, 55.2, 52.9, 45.1, 42.5, 42.5, 29.2, 28.9,24.2, 21.3, 17.7. MS (electrospray) M+1=339. Calculated=339.

[0175]N-[(2′S)-Amino-3′-phenylpropyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(6k). Prepared from N-(tert-butoxy)-L-phenylalanine and(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine according to thegeneral procedure in 44% yield: ¹H NMR (MeOH-d4) δ 7.29 (t, 1H, J=7.4Hz), 7.24-7.06 (m, 5H), 6.75-6.71 (m, 2H), 6.57-6.55(m, 1H), 3.86-3.84(m, 5H), 3.22-3.94 (m, 1H), 2.83-2.69 (m, 2H), 2.63-2.39 (m, 5H),2.35-2.24 (m, 2H), 1.97 (t, 1H, J=6.4 Hz), 1.54 (t, 1H, J=12.7 Hz), 1.27(s, 3H), 0.74 (dd, 3H, J=6.95, 21.04 Hz); ¹³C NMR (MeOH-d4) δ 158.3,153.3, 139.9, 130.6, 130.3, 130.0, 129.6, 129.2, 127.5, 127.1, 118.0,117.9, 113.8, 113.7, 113.2, 65.0, 64.7, 61.0, 57.3, 56.1, 52.9, 52.1,50.5, 49.5, 49.3, 49.2, 49.0, 48.8, 48.7, 48.5, 41.9, 41.5, 40.3, 40.0,39.4, 31.9, 28.0, 16.7. MS (electrospray) M+1=339. Calculated=339.

[0176]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(8). Prepared from compound 6e and 3-(4-hydroxyphenyl)propionic acidaccording to the general procedure above in 74% yield and purified bysilica gel chromatography. The hydrochloride salt was prepared using 1 MHCl in ethyl ether/methanol and precipitated from ethyl acetate: mp136-140° C.; ¹H NMR (free base). CD3OD δ 7.16 (t, J=7.94, Hz, 1H), 7.04(d, J=8.45 Hz, 2H), 6.76 (d, J=7.78 Hz, 1H), 6.72-6.69 (m, 2H), 6.65(dd, J=8.04, 1.76 Hz, 1H), 4.02-3.98 (m, 1H), 3.57 (d, J=12.5 Hz, 1H),3.40 (ddd, J=2.90, 11.6, 13.4 Hz, 2H), 3.03 (dd, J=10.5, 13.4 Hz, 1 Hz),2.84 (t, 7.07 Hz, 2H), 2.60 (t, 7.58 Hz, 2H), 2.43 (dt, J=13.21, 4.9 Hz,1H), 2.36-2.35 (m, 1H), 1.85 (d, J=14.5 Hz, 1H), 1.87-1.76 (m, 1H), 1.42(s, 3H), 0.92 (t, J=6.98 Hz, 6H), 0.815 (d, J=7.53, 3H); ¹³C NMR, CD3ODδ 176.3, 159., 157.7, 153.8, 133.8, 131.3, 131.0, 118.9, 117.1, 114.6,114.2, 62.0, 57.2, 53.2, 52.8, 40.9, 40.3, 33.1, 33.1, 32.5, 31.7, 28.8,20.6, 18.9, 17.3. MS (electrospray) M+1=439. Anal.(C₂₇H₃₉ClN₂O₃.1.5H₂O): C, H, N.

[0177] Compounds cited in Table 1 were removed from the library andpurified by silica gel chromatography. The purity of the library samplewas determined according to the formula [(mg isolated sample/mg crudemass sample)×100].

[0178]N-{(2′R)-[3-(4-Hydroxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(9). Prepared from compound 6f and 3-(4-hydroxyphenyl)propionic acidaccording to the general procedure. Purity (85%); ¹H NMR (MeOH-d4) δ7.83 (s, 3H), 7.13-7.00 (m, 3H), 6.77-6.67 (m, 4H), 6.61-6.57 (m, 1H),3.96-3.89 (m, 1H), 2.86-2.78 (m, 3H), 2.62-2.58 (m, 1H), 2.48 (d, 3H,J=8.0 Hz), 2.36-2.14 (m, 4H), 1.94 (brd, 1H, J=6.3 Hz), 1.76 (sept, 1H,J=5.5 Hz), 1.51 (brd, 1H, J=11.0 Hz), 1.26 (s, 3H), 0.84-0.74 (m, 9H).MS (electrospray) M+1=439. Calculated=439.

[0179]N-{(2′S)-[(3-Phenylpropanamido)-3′-methyl]butyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(10). Prepared from compound 6e and 3-phenylpropionic acid according tothe general procedure. Purity (87%); ¹H NMR (MeOH-d4) δ 7.25-7.22 (m,2H), 7.17-7.13 (m, 4H), 6.82 (s, 1H), 6.76 (d, 1H, J=7.8 Hz), 6.70-6.68(m, 1H), 5.74 (s, 1H), 4.02-3.97 (m, 1H), 2.99-2.87 (m, 2H), 2.74-2.69(m, 1H), 2.64 (brd, 1H, J=1.3 Hz), 2.57-2.40 (m, 6H), 2.27-2.21 (m, 2H),2.17 (s, 3H), 1.92-1.87 (m, 2H), 1.56 (d, 1H, J=13.0 Hz), 1.28 (s, 3H),0.81 (t, 6H, J=6.8 Hz), 0.69 (d, 3H, J=6.8 Hz). MS (electrospray)M+1=423. Calculated=423.

[0180]N-{(2′S)-[3-(3-Hydroxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(11). Prepared from compound 6e and 3-(3-hydroxyphenyl)propionic acidaccording to the general procedure. Purity (84%); ¹H NMR (MeOH-d4) δ7.24-7.23 (m, 1H), 7.13-7.03 (m, 3H), 6.76-6.57 (m, 5H), 3.32-3.29 (m,4H), 2.85-2.17 (m, 8H), 1.97 (brs, 1H), 1.75-1.73 (m, 1H), 1.57 (brd,1H, J=12.3 Hz), 1.28 (s, 3H) 0.863 (t, 6H, J=6.5 Hz), 0.72 (d, 3H,J=7.0). MS (electrospray) M+1=439. Calculated=439.

[0181]N-{(2′S)-[3-(2-Hydroxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(12). Prepared from compound 6e and 3-(2-hydroxyphenyl)propionic acidaccording to the general procedure. Purity (85%); ¹H NMR (CDCl3-d) δ7.04-6.82 (m, 3H), 6.66-6.65 (m, 2H), 6.48-6.39 (m, 3H), 3.97-3.94 (m,1H), 2.87-2.84 (m, 2H), 2.76 (d, 1H, J=11 Hz), 2.56-2.22 (m, 8H),1.94-1.93 (brm, 1H), 1.80 (sextet, 1H, J=6.9 Hz), 1.52 (d, 1H, J=13.3Hz), 1.26 (s, 3H), 0.84 (dd, 6H, J=13.1 Hz), 0.75 (d, 3H, J=6.9 Hz). MS(electrospray) M+1=439. Calculated=439.

[0182]N-{(2′S)-[(4-Hydroxyphenyl)acetamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(13). Prepared from compound 6e and 4-hydroxyphenylacetic acid accordingto the general procedure. Purity (88%); ¹H NMR (MeOH-d4) δ 7.14-7.06 (m,3H), 6.67-6.69 (m, 4H), 6.58 (d, 1H, J=8.1 Hz), 3.95-3.92 (m, 1H),3.32-3.30 (m, 2H), 2.70-2.60 (m, 1H), 2.56-2.47 (m, 1H), 2.41-2.15 (m,6H), 1.90 (brs, 1H), 1.81-1.74 (m, 1H), 1.51 (d, 2H, J=12.5 Hz), 1.25(s, 3H), 0.86 (t, 6H, J=6.7 Hz), 0.67 (d, 3H, J=6.9 Hz). MS(electrospray) M+1=425. Calculated=425.

[0183]N-{(2′S)-[trans-3-(4-Hydroxyphenyl)acrylamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(14). Prepared from compound 6e and trans-3-(4-hydroxyphenyl)cinnamicacid according to the general procedure. Purity (85%); ¹H NMR (MeOH-d4)δ 7.25-7.37 (m, 3H), 7.11-7.04 (m, 1H), 6.79-6.72 (m, 4H), 6.56 (d, 1H,J=9.5 Hz). 6.47 (d, 1H, J=12.7 Hz), 4.10 (m, 1H), 2.80 (m, 1H), 2.64 (m,1H), 2.54-2.26 (m, 5H), 1.95 (m. 2H), 1.56 (d, 1H, J=13.1), 1.28 (s,3H), 0.94 (t, 6H, J=6.8 Hz), 0.70 (d, 3H, J=6.9) MS (electrospray)M+1=437. Calculated=437.

[0184] N-{(2′S)-[3-(4-Fluorophenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(15). Prepared from compound 6e and 3-(4-1 fluorophenyl)propionic acidaccording to the general procedure. Purity (89%); ¹H NMR (MeOH-d4) δ7.23-7.17 (m, 2H), 7.69 (t, 1H, J=8.0 Hz), 6.99-6.92 (m, 2H), 6.76-6.73(m, 2H), 6.60-6.54 (m, 1H), 3.96-3.90 (m, 1H), 2.88 (t, 2H, J=7.7), 2.76(d, 1H, J=10.3 Hz), 2.65-2.32 (m, 8H), 1.97 (brs, 1H), 1.73-1.69 (m,1H), 1.54 (d, 1H, J=12.1 Hz), 1.27 (s, 3H), 0.80 (t, 6H, J=5.8 Hz), 0.71(d, 3H, J=6.9 Hz). MS (electrospray) M+1=441. Calculated=441.

[0185]N-{(2′S)-[3-(3,4-Dihydroxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(16). Prepared from compound 6e and 3-(3,4-dihydroxyphenyl)propionicacid according to the general procedure. Purity (78%); ¹H NMR (MeOH-d4)δ 7.09 (t, 1H, J=7.9 Hz), 6.76-6.73 (m, 2H), 6.67-6.49 (m, 4H), 3.92(brs, 1H), 2.74 (t, 3H, J=7.6 Hz), 2.63-2.59 (m, 1H), 2.51-2.15 (m, 7H),1.94 (brs, 1H), 1.75-1.70 (m, 1H), 1.55 (d, 1H, J=12.1 Hz), 1.27 (s,3H), 0.82 (t, 6H, J=6.4 Hz), 0.71 (d, 3H, J=6.9 Hz). MS (electrospray)M+1=455. Calculated=455.

[0186]N-{(2′S)-[3-(3-Methoxy-4-hydroxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(17). Prepared from compound 6e and3-(3-methoxy-4-hydroxyphenyl)propionic acid according to the generalprocedure. Purity (87%); ¹H NMR (MeOH-d4) d 7.15 (t, 1H, J=7.7 Hz),6.81-6.76 (m, 3H), 6.67 (d, 3H, J=3.3 Hz), 3.98 (brm, 1H), 3.80 (s, 3H),2.86-2.69 (m, 3H), 2.53-2.22 (m, 8H), 1.89 (brs, 2H), 1.55 (d, 1H,J=12.0 Hz), 1.27 (s, 3H), 0.82 (dd, 6H, J=6.6, 3.2 Hz), 0.67 (d, 3H,J=6.9 Hz). MS (electrospray) M+1=469. Calculated=469.

[0187]N-{(2′S)-[3-(3-Methoxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(18). Prepared from compound 6e and 3-(3-methoxyphenyl)propionic acidaccording to the general procedure. Purity (88%); ¹H NMR (MeOH-d4) δ7.30-7.12 (m, 4H), 6.9-6.8 (m, 4H), 3.95 (brs, 1H), 3.76 (s, 3H), 2.96(d, 2H, J=6.8 Hz), 2.86-2.72 (m, 5H), 2.65-2.61 (m, 1H), 2.56-2.14 (m,7H), 1.91(brs, 1H), 1.73-1.71 (m, 1H), 1.52 (d, 1H, J=13.0 Hz), 1.26 (s,3H), 0.81 (t, 6H, J=6.7 Hz), 0.67 (d, 3H, J=6.9 Hz). MS (electrospray)M+1=453. Calculated=453.

[0188]N-{2′-[3-(4-Hydroxyphenyl)propanamido]ethyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(19). Prepared from compound 6a and 3-(4-hydroxyphenyl)propionic acidaccording to the general procedure. Purity (82%); ¹H NMR (MeOH-d4) δ7.13-6.99 (m, 3H), 6.79-6.67 (m, 4H), 6.59 (dd, 1H, J=7.3, 1.8 Hz),3.32-3.25 (m, 3H), 2.83-2.77 (m, 3H), 2.58 (s, 2H), 2.46-2.15 (m, 6H),1.98 (brs, 1H), 1.58 (brd, 1H, J=12.8 Hz), 1.29 (s, 3H), 0.76 (d, 3H,J=7.0 Hz). MS (electrospray) M+1=397. Calculated=397.

[0189]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]propyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(20). Prepared from compound 6c and 3-(4-hydroxyphenyl)propionic acidaccording to the general procedure. Purity (88%); ¹H NMR (MeOH-d4) δ7.77 (s, 1H), 7.08 (t, 1H. J=8.1 Hz), 6.98 (d, 2H, J=8.4 Hz), 6.74-6.67(m, 4H), 6.7 (d, 1H, J=7.5 Hz), 4.03 (dd, 1H, J=6.4 Hz), 2.81-2.70 (m,3H), 2.49 (s, 2H), 2.44-2.26 (m, 4H), 2.16 (td, 2H, J=3.7, 10.9 Hz),1.92-1.89 (m, 1H), 1.50 (d, 1H, J=12.3 Hz), 1.23 (s, 3H), 1.04 (d, 3H,J=6.4 Hz), 0.71 (d, 3H, J=6.9 Hz). MS (electrospray) M+1=411.Calculated=411.

[0190]N-{2′-[3-(4-Hydroxyphenyl)-N-methylpropanamido]ethyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(21). Prepared from compound 6b and 3-(4-hydroxyphenyl)propionic acidaccording to the general procedure. Purity (78%); ¹H NMR (MeOH-d4) δ7:84 (s, 1H), 7.18-7.00 (m, 3H), 6.77-6.69 (m, 4H), 6.60 (d, 1H, J=8.1Hz), 3.47-3.27 (m, 2H), 2.92-2.90 (m, 3H), 2.82-2.77 (m, 3H), 2.67-2.54(m, 3H), 2.47-2.18 (m, 3H), 1.96 (brs, 1H), 1.58-1.49 (m, 3H), 1.27 (d,3H, J=2.91 Hz), 0.73 (t, 3H, J=6.5 Hz). MS (electrospray) M+1=411.Calculated=411.

[0191]N-{(2′S)-[3-(4-Hydroxyphenyl)-N-methylpropanamido]propyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(22). Prepared from compound 6d and 3-(4-hydroxyphenyl)propionic acidaccording to the general procedure. Purity (89%); ¹H NMR (MeOH-d4) δ7.09 (t, 1H, J=7.9 Hz), 6.99 (d, 2H, J=8.2 Hz), 6.78-6.66 (m, 4H),6.58-6.56 (m, 1H), 4.92-4.86 (m, 1H), 2.74 (s, 3H), 2.27-2.17 (m, 2H),1.96-1.95 (brm, 1H), 1.55 (brd, 1H, J=14.3 Hz), 1.27 (s, 3H), 1.02 (d,3H, J=6.7 Hz), 0.66 (d, 3H, J=6.9 Hz). MS (electrospray) M+1=425.Calculated=425.

[0192]N-{(2′S)-[3-(4-Hydroxyphenyl)-N-methylpropanamido]-2′-phenylethyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(23). Prepared according to the general procedure using compound 6j and3-(4-hydroxyphenyl)propionic acid according to the general procedure.Purity (86%); ¹H NMR (MeOH-d4) δ 7.69-7.66 (n, 1H), 7.45-7.42 (m, 1H),7.32-6.97 (m, 7H), 6.76 (d, 1H, J=9.4 Hz), 6.73 (s, 1H), 6.66-6.64 (m,1H), 6.59-6.57 (m, 1H), 6.05 (q, 1H, J=5.5 Hz), 3.00-2.71 (m, 9H),2.65-2.63 (m, 2H), 2.29 (td, 1H, J=4.3, 8.4 Hz), 2.01-2.00 (brm, 1H),1.59 (brd, 1H, J=12.0 Hz), 1.32-1.28 (m, 6H), 0.71 (d, 3H, J=6.9 Hz). MS(electrospray) M+1=487. Calculated=487.

[0193]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]4′-methylpentyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(24). Prepared according to the general coupling procedure (though on a3-mmol scale) using compound 6g and 3-(4-hydroxyphenyl)propionic acid in85% yield. Crude products were then purified by silica gelchromatography using 10-25% methanol in chloroform: ¹H NMR (MeOH-d4) δ7.85 (s, 1H), 7.26-7.06 (m, 6H), 6.97 (d, 2H, J=8.5 Hz), 6.76-6.66 (m,3H), 6.58 (d, 1H, J=7.2 Hz), 4.27 (t, 1H, J=7.3 Hz), 2.84-2.23 (m, 10H),1.93 (brd, 1H, J=7.2 Hz), 1.52 (d, 1H, J=12.0 Hz), 1.25 (s, 3H), 1.05(t, 1H, J=7.2 Hz), 0.74 (d, 3H, J=6.9 Hz); ¹³C NMR (MeOH-d4) δ 164.0,147.5, 143.0, 142.6, 129.0, 122.3, 119.9, 119.6, 119.3, 118.5, 116.5,107.3, 105.5, 103.0, 102.2, 51.6, 46.1, 40.8, 29.4, 29.3, 29.3, 28.7,21.4, 21.0, 17.3.-Anal. (C₂₈H₄₀N₂O₃): C, H, N.

[0194]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]-3′-methylpentyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(25). Prepared according to the general procedure (though on a 3-mmolscale) using compound 6h and 3-(4-hydroxyphenyl)propionic acid in 81%yield. Crude products were then purified by silica gel chromatographyusing 10-25% methanol in chloroform: ¹H NMR (MeOH-d4) δ 7.59 (s, 1H),6.90-6.76 (m, 3H), 6.52-6.45 (m, 3H), 6.36 (d, 1H, J=7.6 Hz), 3.89 (brs,1H), 2.56-2.54 (m, 3H), 2.39-1.95 (m, 9H), 1.70 (brs, 1H), 1.32-1.10 (m,3H), 1.03 (s, 5H), 0.65-0.61 (m, 8H), 0.52-0.42 (m, 3H); ¹³C NMR(MeOH-d4) δ 163.8, 147.5, 146.0, 142.6, 122.2, 119.7, 119.4, 107.4,105.5, 103.1, 102.6, 68.7, 53.7, 46.2, 41.0, 39.4, 39.1, 35.4, 33.4,29.5, 28.9, 28.7, 21.5, 21.2, 17.5, 15.1, 13.3, 11.9. Anal.(C₂₈H₄₀N₂O₃): C, H, N.

[0195]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]-2′-cyclohexylethyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(26). Prepared according to the general procedure (though on a 3-mmolscale) using compound 6i and 3-(4-hydroxyphenyl)propionic acid in 87%yield. Crude products were then purified by silica gel chromatographyusing 10-25% methanol in chloroform: ¹H NMR (MeOH-d4) δ 7.85-7.82 (m,2H), 7.11-6.97 (m, 3H), 6.74-6.56 (m, 5H), 3.99-3.97 (m, 1H), 2.81-2.75(m, 3H), 2.54 (m, 1H), 2.44-2.12 (m, 7H), 1.94 (brs, 1H), 1.54-1.26 (m,3H), 1.25 (s, 3H), 1.02-0.68 (m, 10H); ¹³C NMR (MeOH-d4) δ 164.1, 147.5,146.0, 142.6, 122.2, 119.7, 119.4, 107.3, 105.5, 103.1, 102.5, 68.7,49.4, 45.5, 41.3, 40.9, 29.4, 28.8, 28.4, 21.5, 21.1, 17.4, 15.4. Anal.(C₃₀H₂₄N₂O₃): C, H, N.

[0196]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]-3′-phenylpropyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(27). Prepared according to the general procedure (though on a 3-mmolscale) using compound 6k and 3-(4-hydroxyphenyl)propionic acid in 82%yield. Crude products were then purified by silica gel chromatographyusing 10-25% methanol in chloroform: ¹H NMR (MeOH-d4) δ 7.88(s, 1H),7.12-7.00 (m, 3H), 6.76-6.66 (m, 4H), 6.59-6.55 (m, 1H), 3.90 (m, 1H),2.78 (q, 3H, J=7.0 Hz), 2.62-2.56 (m, 1H), 2.47-2.24 (m, 6H), 1.66-1.50(m, 6H), 1.26 (s, 3H), 1.16-1.03 (m, 3H), 0.88-0.84 (m, 2H), 0.71 (d,3H, J=6.9 Hz); ¹³C NMR (MeOH-d4) δ 164.1, 147.5, 146.0, 142.6, 122.1,119.8, 119.4, 107.3, 105.5, 103.1, 102.6, 68.7, 50.1, 45.6, 41.2, 41.1,31.7, 29.4, 28.8, 21.5, 21.1, 20.3, 18.4, 17.4, 16.8. Anal.(C₃₁H₂₈N₂O₃): C, H, N.

[0197] Opioid Binding Assays. Mu binding sites were labeled using[³H][D-Ala²-MePhe⁴,Gly-ol⁵]enkephalin ([³H]DAMGO) (2.0 nM, SA=45.5Ci/mmol), and delta binding sites were labeled using[³H][D-Ala²,D-Leu⁵]enkephalin (2.0 nM, SA=47.5 Ci/mmol) using rat brainmembranes prepared as described.⁴ Kappa-1 binding sites were labeledusing [³H]U69,593 (2.0 nM, SA=45.5 Ci/mmol) and guinea pig membranespretreated with BIT and FIT to deplete the mu and delta binding sites.⁵

[0198] [³H]DAMGO binding proceeded as follows: 12×75 mm polystyrene testtubes were prefilled with 100 μL of the test drug which was diluted inbinding buffer (BB: 10 mM Tris-HCl, pH 7.4, containing 1 mg/mL BSA),followed by 50 μL of BB, and 100 μL of [³H]DAMGO in a protease inhibitorcocktail (10 mM Tris-HCl, pH 7.4, which contained bacitracin (1 mg/mL),bestatin (100 μg/mL), leupeptin (40 μg/mL), and chymostatin (20 μg/mL).Incubations were initiated by the addition of 750 μL of the preparedmembrane preparation containing 0.2 mg/mL of protein and proceeded for 4to 6 h at 25° C. The ligand was displaced by 10 concentrations of testdrug, in triplicate, 2×. Nonspecific binding was determined using 20 μMlevallorphan. Under these conditions, the K_(d) of [³H]DAMGO binding was4.35 nM. Brandel cell harvesters were used to filter the samples overWhatman GF/B filters, which were presoaked in wash-buffer (ice-cold 10mM Tris-HCl, pH 7.4).

[0199] [³H][D-Ala²,D-Leu⁵]enkephalin binding proceeded as follows: 12×75mm polystyrene test tubes were prefilled with 100 μL of the test drugwhich was diluted in BB, followed by 100 μL of a salt solutioncontaining choline chloride (1 M, final concentration of 100 mM), MnCl2(30 mM, final concentration of 3.0 mM), and, to block mu sites, DAMGO(1000 nM, final concentration of 100 nM), followed by 50 μL of[³H][D-Ala²,D-Leu⁵]enkephalin in the protease inhibitor cocktail.Incubations were initiated by the addition of 750 μL of the preparedmembrane preparation containing 0.41 mg/mL of protein and proceeded for4 to 6 h at 25° C. The ligand was displaced by 10 concentrations of testdrug, in triplicate, 2×. Nonspecific binding was determined using 20 μMlevallorphan. Under these conditions the K_(d) of[³H][D-Ala²,D-Leu⁵]enkephalin binding was 2.95 nM. Brandel cellharvesters were used to filter the samples over Whatman GF/B filters,which were presoaked in wash buffer (ice-cold 10 mM Tris-HCl, pH 7.4).

[0200] [³H]U69,593 binding proceeded as follows: 12×75 mm polystyrenetest tubes were prefilled with 100 μL of the test drug which was dilutedin BB, followed by 50 μL of BB, followed by 100 μL of [³H]U69,593 in thestandard protease inhibitor cocktail with the addition of captopril (1mg/mL in 0.1N acetic acid containing 10 mM 2-mercapto-ethanol to give afinal concentration of 1 μg/mL). Incubations were initiated by theaddition of 750 μL of the prepared membrane preparation containing 0.4mg/mL of protein and proceeded for 4 to 6 h at 25° C. The ligand wasdisplaced by 10 concentrations of test drug, in triplicate, 2×.Nonspecific binding was determined using 1 μM U69,593. Under theseconditions the K_(d) of [³H]U69,593 binding was 3.75 nM. Brandel cellharvesters were used to filter the samples over Whatman GF/B filters,which were presoaked in wash buffer (ice-cold 10 mM Tris-HCl, pH 7.4)containing 1% PEI.

[0201] For all three assays, the filtration step proceeded as follows: 4mL of the wash buffer was added to the tubes, rapidly filtered and wasfollowed by two additional wash cycles. The tritium retained on thefilters was counted, after an overnight extraction into ICN Cytoscintcocktail, in a Taurus-beta counter at 44% efficiency.

[0202] [³⁵S]-GTP-γ-S Binding Assay. Ten frozen guinea pig brains (HarlanBioproducts for Science, Inc, Indianapolis, Ind.) were thawed, and thecaudate putamen were dissected and homogenized in buffer A (3mL/caudate) (Buffer A=10 mM Tris-HCl, pH 7.4 at 4° C. containing 4 μg/mLleupeptin, 2 μg/mL chymostatin, 10 μg/mL bestatin, and 100 μg/mLbacitracin) using a polytron (Brinkman) at setting 6 until a uniformsuspension was achieved. The homogenate was centrifuged at 30,000×g for10 min at 4° C. and the supernatant discarded. The membrane pellets werewashed by resuspension and centrifugation twice more with fresh bufferA, aliquotted into microfuge tubes, and centrifuged in a Tomyrefrigerated microfuge (model MTX 150) at maximum speed for 10 min. Thesupernatants were discarded, and the pellets were stored at −80° C.until assayed.

[0203] For the [³⁵S]GTP-γ-S binding assay, all drug dilutions were madeup in buffer B [50 mM TRIS-HCl, pH 7.7/0.1% BSA]. Briefly, 12×75 mmpolystyrene test tubes received the following additions: (a) 50 μLbuffer B with or without an agonist, (b) 50 μL buffer B with or without60 μM GTP-γ-S for nonspecific binding, (c) 50 μL buffer B with orwithout an antagonist, (d) 50 μL salt solution which contained in bufferB 0.3 nM [³⁵S]GTP-γ-S, 600 mM NaCl, 600 μM GDP, 6 mM dithiothreitol, 30mM MgCl₂, and 6 mM EDTA, and (e) 100 μL membranes in buffer B to give afinal concentration of 10 μg per tube. The final concentration of thereagents were 100 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, 1 mM dithiothreitol,100 μM GDP, 0.1% BSA, 0.05-0.1 nM [³⁵S]GTP-γ-S, 500 nM or 10 μMagonists, and varying concentrations (at least IO differentconcentrations) of antagonists. The reaction was initiated by theaddition of membranes and terminated after 4 h by addition of 3 mLice-cold (4° C.) purified water (Milli-Q uv-Plus, Millipore) followed byrapid vacuum filtration through Whatman GF/B filters presoaked inpurified water. The filters were then washed once with 5 mL ice-coldwater. Bound radioactivity was counted by liquid scintillationspectroscopy using a Taurus (Micromedic) liquid scintillation counter at98% efficiency after an overnight extraction in 5 mL Cytoscintscintillation fluid. Nonspecific binding was determined in the presenceof 10 μM GTP-γ-S. Assays were performed in triplicate, and eachexperiment was performed at least 3×.

[0204] Data Analysis. The data of the two separate experiments (opioidbinding assays) or three experiments ([³⁵S]-GTP-γ-S assay) were pooledand fit, using the nonlinear least-squares curve-fitting languageMLAB-PC (Civilized Software, Bethesda, Md.), to the two-parameterlogistic equation⁶ for the best-fit estimates of the IC₅₀ and slopefactor. The K_(i) values were then determined using the equation:IC₅₀/1+([L]/K_(d)).

[0205] % Inhibition Data for Compounds of Formula (I) in a KappaReceptor Assay R₁ R₂ R₃ (acid) % Inhibition H H PA5 13 H H BA1 20 H HBA2 20 H H BA4 21 H H BA6 32 H H BA8 11 H H BA9 24 H H BA10 28 H H BA12 6 H H BA13  9 H H BA14 11 H H BA16 11 H H BA22  2 H H BA23 13 H H BA24 2 H H BA25  6 H H AA2  1 H H AA4  0 H H PP1  9 H H PP2 23 H H PP3 17 HH PP4  1 H H PP5  8 H H PP6 14 H H PP12 29 H H PP15 19 H H FA1 13 H HFA2  9 H H FA3 50 H H FA4 33 H H FA5 39 H H PA6 27 H H FA7 29 H H FA8 35H H FA9 33 H H FA10  8 H H HA1 20 H H HA2 42 H H HA3  9 H H HA4 15 H HHA5 20 H H OA23  8 H H PB1 37 H H CA2 35 H H CA10 23 H H CA11 13 H HCA12 15 H H PA38 14 H H CA19 10 H H CA20 12 H H CA22 19 H H CA38 27 H HPA9 18 H H PA10  9 H H PA13 25 H H PA15 17 H H PA18 16 H H PA23  9 H HPA27 18 H H PA28  9 H H PA29 10 H H PA32 22 H H PA3 20 H H PA4 11 H HPA7  9 H H PA17 13 H H PA22 19 H H PA8 23 H H NA1 16 H H NA2  6 H H NA313 H H NA4  1 H H NA5 10 H H NA6  2 H H NA7  2 H H NA8 15 H H NA9 26 H HNA10 22 H H NA11 15 H H BA7  2 H H PA38  5 H H AA1  8 H H AA2  6 H H AA4 3 H H PP6 11 H CH₃ BA4 12 H CH₃ BA10 13 H CH₃ BA1  6 H CH₃ CA1  9 H CH₃CA5  6 H CH₃ PA37  5 H CH₃ PA5 11 H CH₃ PA14  0 H CH₃ PA32  0 H CH₃ PP2 0 H CH₃ PP5  0 H CH₃ PP6  0 H CH₃ PP1  0 H CH₃ PP7  0 H CH₃ BA11  0 HCH₃ CA4  0 αi-Pr H BA4  9 αi-Pr H BA5 19 αi-Pr H BA8  0 αi-Pr H BA7  5αi-Pr H BA11  0 αi-Pr H BA12  0 αi-Pr H BA13 26 αi-Pr H BA15  1 αi-Pr HBA19  0 αi-Pr H BA20  0 αi-Pr H BA21  3 αi-Pr H CA1  0 αi-Pr H CA10  0αi-Pr H CA11  0 αi-Pr H CA7  0 αi-Pr H PA5  6 αi-Pr H PA7 14 αi-Pr H PA9 0 αi-Pr H PA10  0 αi-Pr H PA13 10 αi-Pr H PA15  4 αi-Pr H PA18  7 αi-PrH PA22  0 αi-Pr H PA27 18 αi-Pr H PA28  6 αi-Pr H CA16  0 αi-Pr H CA18 0 αi-Pr H PA29  1 αi-Pr H PP1 28 αi-Pr H PP2  3 αi-Pr H PP3 27 αi-Pr HPP4 18 αi-Pr H PP5 20 αi-Pr H PP6 70 αi-Pr H PP7 13 αi-Pr H PP8 17 αi-PrH PP12 23 αi-Pr H PP15 26 αi-Pr H PP16 31 αi-Pr H PP17 43 αi-Pr H CA5  4αi-Pr H CA7 16 αi-Pr H CA12 15 αi-Pr H PA8 21 αi-Pr H PA23  6 αi-Pr HPA32 13 αi-Pr H BA1  3 αi-Pr H CA4  3 αi-Pr H PA18  7 αi-Pr H NA1 14αi-Pr H NA2  3 αi-Pr H NA3 16 αi-Pr H NA4 43 αi-Pr H NA5 61 αi-Pr H NA6 1 αi-Pr H NA7 22 αi-Pr H NA8  3 αi-Pr H NA9 33 αi-Pr H NA10  3 αi-Pr HNA11 34 αi-Pr H BA7 25 αi-Pr H PA38  4 αi-Pr H AA1  3 αi-Pr H AA2  4αi-Pr H AA4 13 αi-Pr H CA2  5 αi-Pr H FA1  5 αi-Pr H FA2  6 αi-Pr H FA3 9 αi-Pr H FA4 17 αi-Pr H FA5 10 αi-Pr H FA6 10 αi-Pr H FA7 10 αi-Pr HFA8 27 αi-Pr H FA9 14 αi-Pr H FA10  6 αi-Pr H HA1  6 αi-Pr H HA2  1αi-Pr H HA3  0 αi-Pr H HA4 10 αi-Pr H HA5 10 αi-Pr H OA23  0 αi-Pr H PB1 7 αi-Pr H PA14  8 βi-Pr H PP4 52 βi-Pr H PP6 11 βi-Pr H PP8 10 βi-Pr HPP12 50 βi-Pr H PP15 24 βi-Pr H PP16  8 βi-Pr H PP17 10 βi-Pr H PP18  5αCH₃ H PP6 11 αCH₃ CH₃ CA1  3 αCH₃ CH₃ CA2  0 αCH₃ CH₃ CA8  0 αCH₃ CH₃CA14  0 αCH₃ CH₃ CA15  1 αCH₃ CH₃ CA19  0 αCH₃ CH₃ CA20 10 αCH₃ CH₃ CA24 5 αCH₃ CH₃ CA28  0 αCH₃ CH₃ CA30  7 αCH₃ CH₃ BA1  7 αCH₃ CH₃ BA4  7αCH₃ CH₃ BA8  8 αCH₃ CH₃ BA13  8 αCH₃ CH₃ BA19  8 αCH₃ CH₃ BA20  5 αCH₃CH₃ BA21  5 αCH₃ CH₃ BA23  6 αCH₃ CH₃ BA25  5 αCH₃ CH₃ PA5  6 αCH₃ CH₃PA8  1 αCH₃ CH₃ PA10  0 αCH₃ CH₃ PA19  0 αCH₃ CH₃ PA21  0 αCH₃ CH₃ PA27 4 αCH₃ CH₃ PA28  0 αCH₃ CH₃ PA29  1 αCH₃ CH₃ PA32  0 αCH₃ CH₃ PA14  0αCH₃ CH₃ PP1  6 αCH₃ CH₃ PP4  2 αCH₃ CH₃ PP5  3 αCH₃ CH₃ PP7  1 αCH₃ CH₃PP8  0 αCH₃ CH₃ PP10  5 αCH₃ CH₃ BAL1  0 αCH₃ CH₃ GAB1  0 αCH₃ CH₃ INP1 0 αCH₃ CH₃ CA13  1 αCH₃ CH₃ PA17  0 αCH₃ CH₃ PA9 10 αCH₃ CH₃ BA24  2αCH₃ CH₃ PP2  5 αCH₃ CH₃ PP3  1 αCH₃ CH₃ PP6  1 αCH₃ CH₃ PA20  4 αPh CH₃CA1  0 αPh CH₃ CA4  0 αPh CH₃ CA9  1 αPh CH₃ CA14  0 αPh CH₃ CA15  3 αPhCH₃ CA19  0 αPh CH₃ CA20  2 αPh CH₃ BA1  3 αPh CH₃ BA2  0 αPh CH₃ BA4  0αPh CH₃ PA14  3 αPh CH₃ PA19  0 αPh CH₃ PP1  4 αPh CH₃ PP2  4 αPh CH₃OA1  9 αPh CH₃ OA3  4 αPh CH₃ CA2  5 αPh CH₃ BA21  7 αPh CH₃ PP3  5 αPhCH₃ GAB1 11 αPh CH₃ BA8  4 αPh CH₃ BA10  0 αPh CH₃ BA15 15 αPh CH₃ PA8 1 αPh CH₃ PA9  0 αPh CH₃ PA10  6 αPh CH₃ PA20  6 αPh CH₃ PA21  9 αPhCH₃ PP6  7 αPh CH₃ PP7  0 αPh CH₃ PP8  0 αPh CH₃ OA2  0

[0206] Amino Alkyl Acids AA 1 1-Piperidine Propionic Acid 157.21 AA 22-N,N-Dimethyl Glycine 103.21 AA 3 3-N,N-Dimethyl Amino Propionic AcidAA 4 4-N,N-Dimethyl Amino Butyric Acid 167.64 Benzoic Acids BA 1 BenzoicAcid 122.12 BA 2 2-Chlorobenzoic Acid 156.57 BA 3 2-AcetamidobenzoicAcid 179.18 BA 4 2-Phenoxybenzoic Acid 214.22 BA 6 3-Chlorobenzoic Acid156.57 BA 8 3-Phenoxybenzoic Acid 214.22 BA 9 3-Hydroxybenzoic Acid138.12 BA 10 4-Chlorobenzoic Acid 156.57 BA 7 4-DimethylaminobenzoicAcid 165.19 BA 12 4-Dodecyloxybenzoic Acid 306.45 BA 13 4-ButoxybenzoicAcid 212.69 BA 14 4-Hydroxybenzoic Acid 138.12 BA 16 4-tert-butylbenzoicAcid 178.23 BA 18 4-Acetamidobenzoic Acid 179.18 BA 19 o-Anisic Acid152.15 BA 20 m-Anisic Acid 152.15 BA 21 p-Anisic Acid 152.15 BA 222-Benzoylbenoic Acid 226.23 BA 23 2-Biphenylbenzoic Acid 98.22 BA 244-Biphenylbenzoic Acid 98.22 BA 25 3-Dimethylaminobenzoic Acid 165.19 BA26 2-Fluorobenzoic Acid 140.11 BA 27 3-Nitrobenzoic Acid 167.12 BA 28o-Tolylic Acid 136.15 BA 29 m-Tolylic Acid 136.15 BA 30 p-Tolylic Acid136.15 BA 31 4-Fluoro-3-nitrobenzoic 185.11 BA 32 3,4-DichlorobenzoicAcid 191.01 BA33 2-Hydroxy Benzoic acid 138.12 BA34 4-Chloro-3-NitroBenzoic Acid 201.57 BA35 4-Flurobenzoic Acid 140.11 BA36 2-Nitrobenzoicacid 167.12 BA37 4-Nitrobenzoic acid 167.12 Cinnamic Acids CA 1a-Methylcinnamic Acid 162.19 CA 2 a-Phenylcinnamic Acid 226.4 CA 32-Bromo-4,5-dimethoxycinnamic Acid 287.11 CA 4 2-Chlorocinnamic Acid182.61 CA 5 2,4-Dichlorocinnamic Acid 217.05 CA 6 3,4-DihydroxycinnamicAcid 180.16 CA 7 2,4-Dimethoxycinnamic Acid 208.21 CA 83,5-Di-tert-butyl-4-hydroxycinnamic Acid 276.37 CA 9 3-FluorocinnamicAcid 166.15 CA 10 2-Hydroxycinnamic Acid 164.16 CA 11 3-HydroxycinnamicAcid 164.16 CA 12 4-Hydroxycinnamic Acid 164.16 CA 13 2-MethoxycinnamicAcid 178.19 CA 14 3-Methoxycinnamic Acid 178.19 CA 15 4-MethoxycinnamicAcid 178.19 CA 16 2-Methylcinnamic Acid 162.19 CA 17 3-MethylcinnamicAcid 162.19 CA 18 4-Methylcinnamic Acid 162.19 CA 193-(1-Naphthyl)acrylic Acid 224.46 CA 20 4-Phenylcinnamic Acid 224.26 CA21 3,4,5-Trimethoxycinnamic Acid 238.24 CA 22 4-Isopropylcinnamic acid190.24 CA23 2,6-Dichloro 218.063 CA24 3-benzyloxy 254.234 CA252-bromo-4,5-dimethoxy 287.12 CA26 2-chloro-6-fluoro 200.6 CA27alpha-methyl-2,4,5-trimethoxy 252.27 CA28 2-n-hexyloxy 250.22 CA295-bromo-2-methoxy 257.09 CA30 2-benzyloxy 254.234 CA31 2,4,5-trimethoxy238.24 CA32 2,6-difluoro 184.14 CA33 2-t-butylthio 236.157 CA342-chloro-5-nitro 227.61 CA35 2,3-dimethoxy 208.21 CA363,5-dit-butyl-4-hydroxy 276.37 CA37 2,5-dimethoxy 208.22 CA38trans-Cinnamic Acid 147 CA39 cis-Cinnamic Acid 147 Fatty Acids FA 1Acetic Acid 60.05 FA 2 Propionic Acid 74.08 FA 3 Pivalic Acid 102.13 FA4 1-Phenyl-1-cyclopentane Acid 162.19 FA 5 1-Phenyl-1-cyclopropane Acid190.24 FA 6 Isovaleric Acid 102.13 FA 7 4-Methylvaleric Acid 116.16 FA 8Cyclopentylacetic Acid 128.17 FA 9 Cyclopentylcarboxylic Acid 114.14 FA10 trans-2-Phenyl-1-cyclopropyl CA 162.19 FA 11 Cyclohexane carboxylicAcid 128.17 Hydroxy Acids HA 1 2-Hydroxy-3-methyl butyric 118.13 HA 22-Hydroxy-2-methyl butyric 118.13 HA 3 3-Hydroxy butyric 104.11 HA 43-Hydroxy-4-trimethylamino butyric 197.66 HA 5 2-Phenyl-3-hydroxypropionic 166.18 Nicotinic Acids NA 1 2(n-Amylthio)nicotinic Acid 225.31NA 2 5-Bromonicotinic Acid 202.01 NA 3 6-Chloronicotinic Acid 157.56 NA4 2-Chloronicotinic Acid 157.56 NA 5 2-(Methylthio)nicotinic Acid 169.2NA 6 Nicotinic Acid 123.11 NA 7 Picolinic Acid 123.11 NA 82-Pyridylacetic Acid HCl 173.6 NA 9 3-Pyridylacetic Acid HCl 173.6 NA 104-Pyridylacetic Acid HCl 173.6 NA 11 2-(Phenylthio)Nicotinic Acid 231.27NA 12 2-Hydroxy-6-methyl Nicotinic 153.14 NA 13 3-(3-pyridyl)acrylicacid 149.15 NA 14 3-(4-pyridyl)acrylic acid 149.15 Propionic Acid PP1Phenyl Propionic 150.18 PP2 3,3-Diphenylpropionic Acid 226.28 PP33-Phenylbutyric Acid 164.2 PP4 3-(2-Hydroxyphenyl)propionic Acid 166.18PP5 3-(3-Hydroxyphenyl)propionic Acid 166.18 PP63-(4-Hydroxyphenyl)propionic Acid 166.18 PP73-(3-Methoxyphenyl)propionic Acid 180.2 PP8 3-(4-Methoxyphenyl)propionicAcid 180.2 PP9 3-(3,4,5-Trimethoxyphenyl)propionic Acid 240.26 PP103-(2-Methoxyphenyl)propionic Acid 180.2 PP113-(2,5-Dimethoxyphenyl)propionic Acid 210.24 PP123-(2-Chlorophenyl)propionic Acid 184.62 PP13 3-(4-Aminophenyl)propionicAcid 165.119 PP14 3-(4-Fluorophenyl)propionic Acid 168.17 PP153-(3,4-Dihydroxyphenyl)propionic Acid 182.18 PP163-(3-Methoxy-4-hydroxyphenyl) 196.2 PP17 3-(3,5-dinotro-4-hydroxyphenyl)256.2 PP18 3-(Pentaflurophenyl)propionic Acid PP193-(4-Bocaminophenyl)propionic Acid 265 PP21 2,2-Diphenylpropionic Acid226.28 Phenylacetic Acid PA 1 4-Aminophenylacetic Acid 151.17 PA 24-Biphenylacetic Acid 288.55 PA 3 2-Bromophenylacetic Acid 215.05 PA 44-Bromophenylacetic Acid 215.05 PA 5 4-(n-Butoxy)phenylacetic Acid208.26 PA 7 3-Chloro-4-hydroxyphenylacetic Acid 186.59 PA 82-Chlorophenylacetic Acid 170.6 PA 9 3-Chlorophenylacetic Acid 170.6 PA10 4-Chlorophenylacetic Acid 170.6 PA 11 2-Chloro-6-fluorophenylaceticAcid 188.59 PA 12 2,4-Dichlorophenylacetic Acid 205.04 PA 132,6-Dichlorophenylacetic Acid 205.04 PA 14 3,4-Dichlorophenylacetic Acid205.04 PA 15 2,5-Dimethoxyphenylacetic Acid 196.2 PA 163,4-Dimethoxyphenylacetic Acid 196.2 PA 17 2,5-Dimethylphenylacetic Acid164.2 PA 18 2,4-Dinitrophenylacetic Acid 226.15 PA 192-Fluorophenylacetic Acid 154.14 PA 20 3-Fluorophenylacetic Acid 154.14PA 21 4-Fluorophenylacetic Acid 154.14 PA 22 2-Hydroxyphenylacetic Acid152.15 PA 23 4-Hydroxyphenylacetic Acid 152.15 PA 242-Methoxyphenylacetic Acid 166.18 PA 25 3-Methoxyphenylacetic Acid166.18 PA 26 4-Methoxyphenylacetic Acid 166.18 PA 272-Methylphenylacetic Acid 150.18 PA 28 3-Methylphenylacetic Acid 150.18PA 29 4-Methylphenylacetic Acid 150.18 PA 30 2-Nitrophenylacetic Acid181.15 PA 31 4-Nitrophenylacetic Acid 181.15 PA 32 Phenylacetic Acid136.15 PA 33 2-Trifluormethylophenylacetic Acid 204.15 PA 343-Trifluoromethylphenylacetic Acid 204.15 PA 353,4,5-Trimethoxyphenylacetic Acid 226.23 PA 36 4-Ethoxyphenylacetic Acid180.22 PA 37 Mesitylacetic acid 178.23 PA 38 4-Dimethyl Amino PA PA 393-Hydroxyphenyl PA PA 40 Diphenyl Acetic

REFERENCES

[0207] (1) Thomas, J. B.; Mascarella, S. W.; Rothman, R. B.; Partilla,J. S.; Xu, H.; McCullough, K. B.; Dersch, C. M.; Cantrell, B. E.;Zimmerman, D. M.; Carroll, F. I. Investigation of the N-substituentconformation governing potency and μ receptor subtype-selectivity in(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists.J. Med. Chem. 1998, 41(11), 1980-1990.

[0208] (2) Mitch, C. H.; Leander, J. D.; Mendelsohn, L. G.; Shaw, W. N.;Wong, D. T.; Cantrell, B. E.; Johnson, B. G.; Reel, J. K.; Snoddy, J.D.; Takemori, A. E.; Zimmerman, D. M.3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines: Opioid antagonists withpotent anorectant activity. J. Med. Chem. 1993, 36(20), 2842-2850.

[0209] (3) Xu, H.; Lu, Y. -F.; Partilla, J. S.; Brine, G. A.; Carroll,F. I.; Rice, K. C.; Lai, J.; Porreca, F.; Rothman, R. B. Opioid peptidereceptor studies. 6. The 3-methylfentanyl congeners RTI-4614-4 and itsenantiomers differ in efficacy, potency, and intrinsic efficacy asmeasured by stimulation of [³⁵S]GTP-γ-S binding using cloned μ-opioidreceptors. Analgesia 1997, 3, 3542.

[0210] (4) Rothman, R. B.; Xu, H.; Seggel, M.; Jacobson, A. E.; Rice, K.C.; Brine, G. A.; Carroll, F. I. RTI-4614-4: an analog of(+)-cis-3-methylfentanyl with a 27,000-fold binding selectivity for muversus delta opioid binding sites. Life Sci. 1991, 48, PL111-PL-116.

[0211] (5) Rothman, R. B.; Bykov, V.; de Costa, B. R.; Jacobson, A. E.;Rice, K. C.; Brady, L. S. Interaction of endogenous opioid peptides andother drugs with four kappa opioid binding sites in guinea pig brain.Peptides 1990, 11, 311-331.

[0212] (6) Rodbard, D.; Lenox, R. H.; Wray, H. L.; Ramseth, D.Statistical characterization of the random errors in theradioimmunoassay dose-response variable. Clin. Chem. 1976, 22, 350-58.

[0213] (7) Takemori et al, J. Pharm. Exp. Ther., 1988, 246 (1), 255-258.TABLE 1 Results of Inhibition Screening of Selected Structural Isomersof Compound 8 Taken from the Library versus Kappa Opioid SelectiveLigand [³H]U69,593

% Inhibition compd R1 R2 X1 X2 S₁ S₂ S₃ at 100 nM  8 i-Pr H CH2 CH2 H HOH 71  9 i-Pr^(a) H CH2 CH2 H H OH 11 10 i-Pr H CH2 CH2 H H H 28 11 i-PrH CH2 CH2 H OH H 20 12 i-Pr H CH2 CH2 OH H H 25 13 i-Pr H CH2 — H H OH 6 14 i-Pr H CH^(b) CH^(b) H H OH 15 15 i-Pr H CH2 CH2 H H F 26 16 i-PrH CH2 CH2 H OH OH 31 17 i-Pr H CH2 CH2 H OCH3 OH 42 18 i-Pr H CH2 CH2 HH OCH3 16 19 H H CH2 CH2 H H OH 11 20 CH₃ H CH2 CH2 H H OH 20 21 H CH₃CH2 CH2 H H OH  0 22 CH₃ CH₃ CH2 CH2 H H OH  1 23 C₆H₅ CH₃ CH2 CH2 H HOH  7 DMSO  4

[0214] TABLE 2 Radioligand Binding Data for 8 and Related Compounds atMu, Delta, and Kappa Opioid Receptor Assays

Ki (nM ± SD) (−n_(H)) compd R [³H]DAMGO [³H]DADLE [³H]U69,593 μ/κ δ/κ 8i-Pr 393 ± 13.3 >5700 6.91 ± 0.55 57 >824 (0.89 ± 0.02) (0.81 ± 0.05) 24i-Bu 398 ± 72.3 NA 89.3 ± 7.03 4.5 (0.91 ± 0.16) (0.78 ± 0.05) 25 sec-Bu421 ± 30.5 NA 8.84 ± 0.30 47 (0.91 ± 0.06) (0.87 ± 0.02) 26 c-Hex 234 ±25.2 NA 83.1 ± 5.7 2.8 (0.84 ± 0.08) (0.79 ± 0.04) 27 Benzyl 9.6 ± 1.18NA 54.6 ± 3.5 0.17 (0.89 ± 0.09) (0.86 ± 0.04) 5a^(a) 0.74 ± 0.05 322 ±38.1 122 ± 11.9 0.006 2.6 (0.89 ± 0.09) (0.75 ± 0.09) (0.52 ± 0.07)1(nor- 47.2 ± 3.3 42.9 ± 11 0.28 ± 0.07 181 150 BNI)^(b,c)naltrexone^(b) 1.39 ± 0.40 94.9 ± 6.6 4.71 ± 0.12 0.30 20.1 (0.94 ±0.08) (1.01 ± 0.09) (1.05 ± 0.08)

[0215] TABLE 3 Inhibition by Antagonists of [³⁵S]GTPγS Binding in GuineaPig Caudate Stimulated by DAMGO (μ), SNC80 (δ), and U69,593 (κ)Selective Opioid Agonists. Ki (nM ± SD) (-n_(H))^(a) Compd DAMGO^(b)SNC80^(c) U69,593^(d) 8 7.25 ± 0.52  450 ± 74.1 4.70 ± 0.56 (1.11 ±0.08) (1.05 ± 0.17) (1.38 ± 0.19) 5a^(e) 0.039 ± 0.003  1.48 ± 0.094 1.04 ± 0.061 (1.06 ± 0.07) (1.19 ± 0.08) (1.07 ± 0.06) 1, nor-BNI 16.75± 1.47  10.14 ± 0.96  0.038 ± 0.005 (1.02 ± 0.09) (1.18 ± 0.12) (0.97 ±0.12) naltrexone 0.93 ± 0.21 19.3 ± 2.25 2.05 ± 0.21 (1.03 ± 0.22) (1.05± 0.17) (1.38 ± 0.19)

[0216] Analyses Appendix

[0217]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]-3′-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(8).

[0218] Anal. calcd for C₂₇H₃₉ClN₂O₃.1.5H₂O: C, 64.59, H, 8.43; N, 5.58.Found: C, 64.35; H, 8.12; N, 5.38.

[0219]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]-4′-methylpentyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(24).

[0220] Anal. calcd for C₂₈H₄₀N₂O₃: C, 74.30, H, 8.91; N, 6.19. Found: C,74.12; H, 9.22; N, 6.30.

[0221]N-[(2′S)-(3-(4-Hydroxyphenyl)propanamido]-3′-methylpentyl)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(25).

[0222] Anal. calcd for C₂₈H₄₀N₂O₃: C, 74.30, H, 8.91; N, 6.19. Found: C,74.02; H, 9.20; N, 6.25.

[0223]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]-2′-cyclohexylethyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(26).

[0224] Anal. calcd for C₃₀H₄₂N₂O₃: C, 75.28, H, 8.84; N, 5.85. Found: C,75.18; H, 8.96; N, 5.97.

[0225]N-{(2′S)-[3-(4-Hydroxyphenyl)propanamido]-3′-phenylpropyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine(27).

[0226] Anal. calcd for C₃₁H₃₈N₂O₃: C, 76.51, H, 7.87; N, 5.76. Found: C,76.15; H, 7.99; N, 5.89.

Example 2 N-substituted(±)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-hydroxyphenyl)-10a-methylbenzo[g]isoquinolines

[0227] Summary

[0228] Potent, opioid receptor pure antagonist activity has beendemonstrated in the N-substituted(±)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-hydroxyphenyl)-10a-methylbenzo[g]isoquinolines,7 and 8 (FIG. 8). These compounds share many of the characteristicsidentified with the phenylpiperidine antagonists includingN-susbstituent mediated potency and a lack of N-susbstituent mediatedantagonism. Also, like the phenylpiperidines, 7 and 8 display a strongpreference for mu and kappa versus delta opioid receptor binding. Unlikethe phenylpiperidines however, the benzoisoquinoline system displays astronger preference for the kappa versus the mu opioid receptor and alower overall potency relative to typicaltrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine antagonists. Togetherthis data suggests a common site of action within the opioid receptorsfor compounds 7 and 8 and thetrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines.

[0229] Chemistry

[0230] The N-methyl and N-phenethyl derivatives of(±)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-hydroxyphenyl)-10a-methylbenzo[g]isoquinoline(7 and 8, respectively) were prepared starting from tetrahydropyridine(9) according to the method illustrated in FIG. 8.¹ Accordingly, 9 wasdeprotonated with sec-butyl lithium followed by alkylation withα,α′-dichloroxylene. This material was not isolated but was immediatelycyclized with NaI in refluxing acetonitrile and reduced with sodiumborohydride to provide intermediate 10 in 23% yield. The N-methylderivative (7) was then available via O-demethylation employingrefluxing HBr in acetic acid. The N-phenylethyl derivative (8) wasprepared from 10 by N-demethylation using phenylchloroformate inrefluxing toluene followed by subjecting the crude carbamate torefluxing HBr in acetic acid to cleave the urethane and deprotect thephenol. Conversion of this material to the desired compound (8) wasaccomplished by coupling with phenyl acetic acid usingbenzotriazol-1-yl-oxy-tris-(dimethylamino)phosphoniumhexafluorophosphate (BOP reagent) followed by reduction of the resultingamides using borane in tetrahydrofuran in 2.2% overall yield.

[0231] Results and Discussion

[0232] Both initial studies and work conducted in this laboratory haveprovided strong evidence that the antagonist activity of someN-substituted piperidine compounds is expressed via a phenylequatorial/piperidine chair receptor-ligand interaction as illustratedin FIG. 9b. ² This stands in contrast to the phenylaxial/piperidinechair conformation exhibited by naltrexone (FIG. 9a). Thebenzoisoquinoline system (FIG. 9c), where a bridge connects carbons 3and

[0233] 4 in the piperidine ring, was selected for study because itsstructure could potentially maintain the proposed active conformation ofthe phenylpiperdines as well as provide sites for further structuralelaboration. Compounds 7 and 8 were therefore synthesized and tested inboth binding and functional assays to establish the overall effect ofthis structural change on antagonist activity and potency.

[0234] The radioligand binding data for the N-methyl and N-phenethylderivatives of(±)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-hydroxyphenyl)-10a-methylbenzo[g]isoquinolines(7 and 8, respectively) are provided in Table 4. For comparison, theradioligand binding assay data for the parent ligands 5 and 6 are givenin Table 5.³ As these data sets are from different assays, the bindingdata obtained for naltrexone (3) is provided as a reference standardfrom both sets of assays. Inspection of the data reveals a fundamentalshift in the receptor binding preference of the benzoisoquinolines infavor of the kappa receptor relative to the phenylpiperidines whichtypically show greater potency at the mu receptor. However, the overallpreference for mu/kappa binding relative to delta binding is preserved(the phenylpiperidines typically show the least preference for the deltareceptor, data not shown). Increasing the size of the N-substituent(conversion of 7 to 8) provides an overall increase in potency at allreceptors, a feature shared by conversion of the phenylpiperidine 5 to6. The later information together with the general receptor bindingpreferences suggests that the benzoisoquinoline antagonists probablyinteract with the same subsites within the opioid receptors as do thephenylpiperidines, but the addition of the 3,4 bridge leads to both anincrease in affinity for the kappa receptor as well as a loss ofaffinity for the mu receptor relative to the phenylpiperidineantagonists.

[0235] In the functional assay shown in Table 6, compounds 7 and 8displayed a pattern of activity consistent with the radioligand bindingassay. Thus, inhibition of agonist stimulated [³⁵S]GTPγS binding inguinea pig caudate by 7 and 8, a measure of functional antagonistactivity,⁴ was greatest against U69,593 (kappa receptor) with thepotency demonstrated against DAMGO (mu receptor) being only slightlyless. The ability to inhibit SNC80 (delta receptor) stimulated[³⁵S]GTPγS binding war significantly lower. As in the previous assay,increasing the size of the N-substituent lead to an increase in potency.Importantly, neither the N-methyl derivative 7 nor the N-phenethylderivative 8 stimulated [³⁵S]GTPγS binding when tested at concentrationsas high as 1 μM; the benzoisoquinoline structure therefore retainsopioid pure antagonist activity.

[0236] In terms of potency, both 7 and 8 demonstrate a decreasedaffinity for all of the opioid receptors relative to some of the morepotent phenylpiperidine antagonists. The source of this loss of activitycannot be immediately established since several explanations exist. Itis possible that these compounds have greater preference for a phenylaxial/piperidine chair conformation relative to the phenylpiperidines,though it has been found that 8 exists in thephenylequatorial/piperidine chair conformation in the solid state (FIG.10). More likely, the lower potency results from a lack of activity ofone of the enantiomers of 6. Hugh eudismic ratios are observed in mostclasses of opioid ligands.

[0237] In summary, potent opioid receptor pure antagonist activity wasdemonstrated for(+)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-hydroxyphenyl)-2-phenethyl-10a-methylbenzo[g]isoquinoline(8). Compounds 7 and 8 share many of the characteristics identified withthe phenylpiperidine antagonists including N-substituent mediatedpotency and a lack of N-substituent mediated antagonism. Also, theseligands display a strong preference for mu and kappa versus deltabinding. Unlike the phenylpiperidines, the benzoisoquinolines display astronger preference for the kappa versus the mu receptor and a loweroverall potency as, a racemic mixture, relative to typicaltrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine antagonists. Togetherthis data suggests both a common site of action within the opioidreceptors for, compounds 7 and 8 and thetrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines.

[0238] Experimental

[0239] Melting points were determined on a Thomas-Hoover capillary tubeapparatus and are not corrected. Elemental analyses were obtained byAtlantic Microlabs, Inc. and are within ±0.4% of the calculated values.¹H and ¹³C NMR were determined on a Bruker WM-250 spectrometer usingtetramethylsilane as an internal standard. Radial chromatography wasperformed on a Harrison Research Chromatotron model 7924T. All reactionswere followed by thin-layer chromatography using Whatman silica gel 60TLC plates and were visualized by UV or by charring using 5%phosphomolybdic acid in ethanol. All solvents were reagent grade.Tetrahydrofuran and diethyl ether were dried over sodium benzophenoneketyl and distilled prior to use. α,α′-Dichloroxylene, purchased fromAldrich Chemical Co., was recrystallized from hexane prior to use.

[0240](±)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-methoxyphenyl)-2,10a-dimethylbenzo[g]isoquinoline(10): To a dry three-neck round-bottomed flask was charged 500 mg (2.3mmol) of tetrahydropyridine (9) (CAUTION: read reference 12 andreferences cited therein) and 20 mL dry THF. This was cooled to −78° C.,and to this was added 2.4 mL (3.12 mmol) s-BuLi (1.3M in cyclohexane)via a syringe over 5 min. The flask was then warmed to −0° C. and agedfor 10 min. The flask was then cooled to −78° C. and cannulated into amixture of 40 mL dry ethyl ether and 1.3 g (7.59 mmol) α,α′-dichloroxylene at −50° C. over 20 min. This was aged for 20 min and thenquenched with ice-cold 1N HCl. The contents of the flask were thentransferred to a separatory funnel with ice-cold ether-and ice-cold 1NHCl. The aqueous layer was removed and stored in an ice bath while theorganic layer was twice extracted with ice-cold 1N HCl. The combinedaqueous layers were placed into a new separatory funnel and extractedtwice with ice-cold ethyl ether to remove α,α′-diochloroxylene. Theaqueous layer was then made basic with 50% NaOH at first and finallysaturated NaHCO₃ to pH 10. The aqueous layer was then extracted 3 timeswith ice-cold ethyl ether and then discarded. The ether extracts weredried over K₂CO₃ and then filtered into a round-bottom flask and thesolvent removed on the rotavap at 0° C. After all of the solvent wasremoved, the residue was dissolved in 40 mL sieve dried CH₃CN, and tothis was added 870 mg NaI and 650 mg K₂CO₃. The flask was then attachedto a reflux condenser and a heating mantle and the system heated underreflux for 3 h. After this time, the flask was cooled to roomtemperature and filtered. The solvent was then removed on a rotavap andthe residue dissolved in 40 mL punctilious ethanol. To this mixture wasadded 750 mg NaBH₄ in one portion and the mixture allowed to stirovernight. On the following day, 1N HCl was added to this mixture untilno further evolution of hydrogen was observed. This was stirred for 10min, and then 50% NaOH and water were added until the mixture was clearand basic. The volatiles were then removed on a rotavap, and the residuewas extracted 3 times with 1:1 ethyl ether:ethyl acetate. This was driedover K₂CO₃ and Na₂SO₄. After filtration and solvent removal, a smallportion of the crude residue was dissolved in CHCl₃ and spotted on asilica gel plate. Elution with 50% CMA-80 (80 CHCl₃:18 MeOH:2NH₄OH) inCHCl₃ revealed a compound in the mixture that gave a pale spot whendipped in 5% PMA in EtOH at about 0.75 Rf. This is the tertiary amineproduct. No other tertiary amines were observed in the mixture ¹H NMR ofthe crude mixture revealed the desired product as well as startingmaterial (9) and other undesired products. Chromatography on silica gelusing 12.5% CMA-80 in CHCl₃ gave the desired product in the earlyfractions just behind the solvent front but not in the solvent front.This gave 115 mg of the desired product as a slightly yellow oil. Yield15.5%.

[0241]¹H NMR (CDCl₃) δ 0.993 (s, 3H); 1.404 (ddd, 1H, J=13.7, 2.6, 2.6Hz); 2.149 (d, 1H, J=11.6 Hz); 2.229 (d, 1H, J=17.0 Hz); 2.240 (s, 3H);2.310 (dd, 1H, J=11.6, 1.5 Hz); 2.379 (ddd, 1H, J=12.1, 12.1, 3.2 Hz);2.646 (d, 1H, J=17.0 Hz); 2.862 (dd, 1H, J=13.7, 4.7 Hz); 2.885 (d, 1H,J=18.3 Hz); 2.962 (m, 1H); 3.570 (d, 1H, J=18.3 Hz); 3.634 (s, 3H);6.715 (ddd, 1H, J=8.1, 2.5, 0.9 Hz); 6.839 (m, 2H); 7.048 (d, 1H, J=7.6Hz); 7.197-7.080 (m, 4H). ¹³C NMR (CDCl₃) δ 158.9, 148.9, 135.9, 135.6,128.6, 128.36, 128.0, 125.9, 125.5, 120.0, 113.9, 110.8, 64.04, 54.9,52.2, 46.6, 40.6, 40.11, 35.98, 31.5, 24.4.

[0242](±)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-hydroxyphenyl)-2,10a-dimethylbenzo[g]isoquinoline(7): To a 10 mL single-necked flask was added 100 mg (0.31 mmol) of(j)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-methoxyphenyl)-2,10a-dimethylbenzo[g]isoquinoline(10) and 0.8 mL of glacial acetic acid and 0.8 mL of 48% HBr. Thismixture was heated under reflux for 18 h and then cooled to roomtemperature. The pH was then adjusted to 10 with cooling starting with50% NaOH and finishing with saturated NaHCO₃. This was extracted 2 timeswith CHCl₃ and 2 times with 3:1 n-butanol:toluene. Both extracts weredried over K₂CO₃, and then the solvent was removed. The material fromboth extracts was examined by ¹H NMR and was shown to contain thedesired product. The material from the CHCl₃ layer was chromatographedon silica gel eluting with 25% CMA-80 in CHCl₃. This gave 27 mg of thedesired product (7) (28% yield). The residue was dissolved in MeOH, andto this was added 3 equivalents of 1N HCl in dry ethyl ether. Thesolvents were removed, and the residue crystallized from ether/MeOH. Thebutanol extracts contained 45 mg of the desired material giving anoverall yield of 74.6%. MP ° C. 270-275 (dec). Anal. Calcd forC₂₁H₂₆NOCl.0.25H₂O: C, 65.54; H, 7.20; N, 3.64. Found: C, 65.86; H,7.15; N, 3.42. ¹H NMR (DMSO) δ 1.014 (s, 3H); 1.587 (d, 1H, J=14.3 Hz);2.072 (s, 3H); 2.358 (d, 1H, J=17.4 Hz); 2.498 (d, 1H, J=17.4 Hz); 2.734(s, 3H); 2.924-2.792 (m, 3H); 3.113 (d, 1H, J=13.1 Hz); 3.602 (d, 1H,J=18.78 Hz); 6.562 (d, 1H, J=8.0 Hz); 6.611 (m, 2H); 6.993 (t, 1H, J=7.5Hz); 7.081 (d, 1H, J=7.5 Hz); 7.148 (t, 1H, J=7.8 Hz); 7.269-7.193 (m,2H); 9.30 (s, 1H); 9.898 (bs, 1H). ¹³C NMR (DMSO) δ 156.7, 146.4, 135.5,133.3, 128.5, 128.4, 128.2, 126.2, 125.7, 117.6, 114.3, 113.5, 59.2,49.4, 38.6, 35.4, 35.2, 31.0, 28.7, 22.8.

[0243](±)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-hydroxyphenyl)-2-phenethyl-10a-methylbenzo[g]isoquinoline(8): To 300 mg (0.93 mmol) intermediate (10) was added 5 mL dry toluenefollowed by heating to 80° C. To this was added 0.23 mL (1.86 mmol)distilled phenylchloroformate dropwise via syringe. A precipitateformed, and the mixture was heated at reflux for 5 h. The mixture wascooled to room temperature and washed 3 times with 1N NaOH and driedover sodium sulfate. ¹H NMR of the crude mixture indicated that nostarting material was present (no N-methyl signal at 2.25 ppm). Thecrude mixture was then dissolved in 4 mL glacial acetic acid and 4 mL48% HBr. This was heated at reflux for 18 h followed by addition ofwater and methyl t-butyl ether (MTBE). The aqueous layer was removed andextracted two more times with MTBE to remove phenol. The aqueous layerwas then pH adjusted to 10 using 50% NaOH and saturated sodiumbicarbonate and extracted 3 times with 3:1 methylenechloride:tetrahydrofuran (THF) and the organic layer dried over sodiumsulfate. Following removal of solvent, this highly polar material wasdissolved in 15 mL THF, and to this was added 442 mg (1 mmol) BOPreagent, 0.4 mL triethylamine (2.2 mmol), and 136 mg (1 mmol) phenylacetic acid. This was stirred for 3 h and then diluted with ethyl ether,40 mL, and washed sequentially with 15 mL water, 1N HCl, saturatedsodium bicarbonate, and brine. The solution was dried over sodiumsulfate and the solvent removed on a rotary evaporator. The material wasthen dissolved in chloroform and filtered through silica gel to removehighly colored polar impurities to give 142 mg relatively cleanmaterial. ¹H NMR of this crude material indicated the presence ofrotamers typical of piperidine amides and urethanes. Reduction of thiscompound was accomplished by dissolving in dry THF followed by additionof 1.16 mL of 2M borane dimethylsulfide in THF. After heating for 3 h,the mixture was cooled to room temperature, and 2 mL methanol was addedand stirred for 1 h. After this time, 1.16 mL 1N HCl in ether was addedand stirred for 1 h. The solvent was then removed on a rotary evaporatorand the crude mixture dissolved in chloroform, saturated sodiumbicarbonate, and water. The pH was adjusted to 10 and the organic layerwashed 3 times with water and then dried over sodium sulfate. The cruderesidue was chromatographed on silica gel using 0-10% MeOH in chloroformas eluent, and this material was crystallized from MeOH/ether as its HClsalt to give 55.8 mg of the desired material (0.137 mmol) or 2.2%overall yield. MP ° C. 255-265 (dec). Anal. Calcd for C₂₈H₃₂NOCl.0.5H₂O:C, 75.91; H, 7.51; N, 3.16. Found: C, 75.93;, H, 7.53; N, 3.17.1H NMR(DMSO) δ 10.06 (br s, 1H); 9.34 (s, 1H); 7.30 (dd, 2H, J=8.1 Hz, 8.1Hz); 7.22 (m, 5H); 7.15 (dd, 1H, J=7.7 Hz, 7.7 Hz); 7.08 (d, 1H, J=7.7Hz); 6.63 (s, 1H); 6.62 (d, 1H, J=8.1 Hz); 6.55 (d, 1H, J=8.1 Hz); 3.59(d, 1H, J=18.9 Hz); 3.50 (d, 1H, J=12.1 Hz); 3.32 (m, 4H); 3.11 (ddd,1H, J=5.1 Hz, 12.1 Hz, 12.1 Hz); 3.02 (ddd, 1H, J=5.1 Hz, 12.1 Hz, 12.1Hz); 2.87 (m, 3H); 2.50 (d, 1H, J=17.4); 2.42 (d, 1H, J=17.4); 1.62 (d,1H, J=14.3); 1.08 (s, 3H). ¹³C NMR (DMSO) δ 156.72, 146.44, 137.23,135.45, 133.38, 128.63, 128.59, 128.56, 128.52, 128.19, 126.71, 126.39,125.72, 117.55, 114.33, 113.51, 57.27, 57.18, 48.22, 39.46, 38.66,35.40, 35.21, 29.45, 28.59, 23.06.

REFERENCES

[0244] (1) Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zinmerman, D. M.;Robey, R. L. Application of metalated enamines to alkaloid synthesis. Anexpedient approach to the synthesis of morphine-based analgesics. J. Am.Chem. Soc. 1980, 102, 5955-5956. WARNING: Read the backgroundinformation relating to analogs of MPTP (i.e., 9) including Zimmerman etal., J. Med. Chem., 1986, 29, 1517-1520, and references cited therein.

[0245] (2) Zimmerman, D. M.; Smits, S.; Nickander, R. Furtherinvestigation of novel 3-methyl-4-phenylpiperidine narcotic antagonists.In Proceedings of the 40th Annual Scientific Meeting of the Committee onProblems of Drug Dependence, 1978, pp. 237-247.

[0246] (3) Mitch, C. H.; Leander, J. D.; Mendelsohn, L. G.; Shaw, W. N.;Wong, D. T.; Zimmerman, D. M.; Gidda, S. J.; Cantrell, B. E.; Scoepp, D.D.; Johnson, B. G.; Leander, J. D. J. Med. Chem. 1994, 37, 2262-2265.

[0247] (4) Xu, H.; Lu, Y. -F.; Partilla, J. S.; Brine, G. A.; Carroll,F. I.; Rice, K. C.; Lai, J.; Porreca, F.; Rothman, R. B. Opioid peptidereceptor studies. 6. The 3-methylfentanyl congeners RTI-4614-4 and itsenantiomers differ in efficacy, potency, and intrinsic efficacy asmeasured by stimulation of [³⁵S]GTP-γ-S binding using cloned μ-opioidreceptors. Analgesia 1997, 3, 3542. TABLE 4 Radioligand Binding Resultsin Mu, Delta, and Kappa Opioid Receptor Assays K_(i) (nM ± SD) Compound[³H]DAMGO^(a) [³H]DADLE^(b) [³H]U69,593^(c) 7 297 ± 23  >5710 166 ± 15 (1.02 ± 0.07) (0.87 ± 0.06) 8 11.2 ± 2.7  1270 ± 106  9.8 ± 1.7 (0.56 ±0.07)  (1.14 ± 0.099) (0.69 ± 0.07) 3, naltrexone 1.39 ± 0.40 94.9 ±6.6  4.71 ± 0.12 (0.94) (1.01) (1.05)

[0248] TABLE 5 Affinities of the 4-Phenylpiperidine Antagonists for theμ and κ Opioid Receptors^(a) K_(i) (nM) Compd [³H]Nal^(b) [³H]EKC^(c) 580 833 6 1.5 52 3, naltrexone 0.56 3.9

[0249] TABLE 6 Inhibition by Antagonists of [³⁵S] GTPγS Binding inGuinea Pig Caudate Stimulated by the Opioid Receptor Subtype-SelectiveAgonists, DAMGO (μ), SNC80 (δ), and U69,593 (κ). K_(i) (nM ± SD) (N)Compound DAMGO SNC80^(a) U69,593 7  119 ± 7.93  222 ± 30.7 52.60 ± 6.38 (0.94 ± 0.06) (0.78 ± 0.09) (1.10 ± 0.14) 8   10 ± 0.91  184 ± 24.3 6.61± 0.57 (0.89 ± 0.06) (0.78 ± 0.09) (1.01 ± 0.08) 1, naltrexone 0.930 ±0.21  19.3 ± 2.25 2.05 ± 0.21 (1.00 ± 0.22) (1.13 ± 0.14) (0.76 ± 0.05)

[0250] This Example is described in Thomas et al, Bioorganic andMedicinal Chemistry Letters 8 (1998) 3149-3152, incorporated herein byreference.

Example 3 Opioid Receptor Antagonists

[0251] Summary

[0252] Two sets of novel opioid receptor antagonist pharmacophores havebeen prepared and demonstrated from a model of opioid antagonistbinding. One is based on a rigid 5-phenylmorphan nucleus and the otheron a more flexible benzoisoquinoline nucleus. Using modifications ofthese systems and by comparisons with the relatedtrans-3,4-dimethyl-4-(3-hydoxyphenyl) piperidines, provides strongevidence supporting the hypothesis that this class of antagonist bindsthe opioid receptors in a phenyl equatorial mode and that thetrans-3-methyl substituent (phenyl piperidine numbering) is an importantelement for conversion of agonists into antagonists.

[0253] Chemistry

[0254] The β-5-(3-hydroxyphenyl) morphans were prepared by the methodshown in FIG. 11. Deprotonation of the known compound 10 with sec-butyllithium followed by alkylation with allyl bromide cleanly providedintermediate 11 in quantitative yield. This compound was then cyclizedprovide 12 in 90% yield as a 2.5:1 mixture of diastereomers. Furtherexperimentation established conditions which changed the ratio of12a:12b to 10:1. Compounds 13a,b were then readily available via enaminereduction followed by separation using radial chromatography. The majorisomer 13 was then O-demethylated to give 14. Since elucidation of thestereochemistry was not straightforward using NMR techniques, crystalsof the HCl salt of 14 are shown by X-ray analysis to possess the desired9β-methyl stereochemistry.

[0255] Compound 13 was also converted to the N-phenylethyl compound 18.N-Demethylation of 13 gave 15 which on O-demethylation yielded 16.Compound 16 was then converted to the N-phenethyl derivative (18) by thetwo step procedure involving coupling of 16 with phenylacetic acidfollowed by borane-dimethylsulfide reduction of the intermediate amide17.

[0256] The benzoisoquinoline compound (20) was also prepared startingfrom compound 10 according to the method illustrated in FIG. 12.Accordingly, 10 was deprotonated with sec-butyl lithium followed byalkylation with α,α′-dichloro-xylene to give intermediate 19 which wasnot isolated but was immediately cyclized with NaI and reduced toprovide compound 20 in 13% yield. O-Demethylation of 20 using hydrogenbromide in acetic acid yielded 21. The structure was established using acombination of NMR techniques.

[0257] Biological Assay Results

[0258] The new compounds 14, 18, and 21 were shown to bind the opioidreceptors and also were shown to be pure antagonists. The datasupporting these conclusions is presented in Tables 7 and 8.

[0259] Discussion

[0260] The radioligand binding data in Table 7 show that compounds 14,18, and 21 have affinity for the opioid receptors. 18 is more potentthan 14. The data in Table 8 shows that all three compounds are pureantagonists.

[0261] Experimental

[0262] All of the solvents used were reagent grade with the exception ofdiethyl ether and THF in reactions and these were distilled fromsodium/benzophenone ketyl. NMR spectra were collected on both a 250 MHzand a 500 MHz Bruker spectrometer. The melting points reported below areuncorrected.

[0263]1,2,3,4-Tetrahydro-4-allyl-1,5-dimethyl-4-(m-methoxyphenyl)pyridine (5):To a solution of 500 mg (2.3 mmol) of tetrahydropyridine 10 in 15 mL ofTHF at 42° C. was added s-BuLi in cyclohexane (1.3M, 2.9 mmol). After 1h, allyl bromide (2.3 mmol) was added, and the color of the solutionchanged from dark red to yellow. After been stirred for 1 hour at −42°C., the mixture was allowed to warmed to 0° C. and then quenched withwater (10 mL). Diethyl ether (10 mL) was added and the aqueous layer wasextracted with ether (2×). The combined ether layers were washed withwater (10 mL), saturated NaHCO₃, brine and dried over Na₂SO₄.Evaporation of solvent afforded 590 mg (100%) of crude 11. The crudeproduct was used directly in the next step without further purification.¹H NMR (CDCl₃) δ 7.26 (m, 1H), 7.01 (m, 2H), 6.74 (m, 1H), 5.89 (s, 1H),5.82 (m, 1H), 5.13 (m, 2H), 3.80 (s, 3H), 2.68-2.40 (m, 3H), 2.55 (s,3H), 2.22 (m, 1H), 1.66 (m, 2H), 1.52 (s, 3H). ¹³C NMR (CDCl₃) δ 159.2,151.1, 136.7, 135.8, 128.7, 119.8, 117.4, 114.3, 110.1, 107.7, 55.1,46.1, 43.1, 43.0, 41.7, 36.4, 17.3.

[0264](1S*,5R*,9R*/S*)-2,9-Dimethyl-5-(m-methoxyphenyl-2-azabicyclo[3,3,1]non-3-ene(12a/b): A solution of 300 mg (1.17 mmol) of 11 in 6 mL of 85%H₃PO₄/HCO₂H (1:1) was stirred at room temperature for 72 h. Theresulting dark brown mixture was diluted with water (6 mL) and cooled inice bath while NaOH (25% w/w) was added until pH-8. The aqueous solutionwas extracted with CHCl₃ (3×). The combined organic layers was washedwith aqueous NaHCO₃ and brine and dried over Na₂SO₄. Evaporation of thesolvent gave 270 mg (90%) of crude products 12a and 12b in a ratio of2.5:1. The crude products were used directly in the next step withoutfurther purification. ¹H NMR (CDCl₃) of the mixture: 67.24-6.70 (m, 4H),6.16 (d, 1H, J=9.2 Hz), 4.34 (d, 1H, J=7.0 Hz), 4.13 (d, 1H, J=9.1 Hz),3.80 (s, 3H), 2.80 (s, 3H), 3.10-1.40 (m, 8H), 0.74 (d, 3H, J=8.6 Hz),0.57 (d, 3H, J=8.1 Hz).

[0265](1S*,5R*,9R*/S*)-2,9-Dimethyl-5-(m-methoxyphenyl)-2-azabicyclo[3,3,1]nonane(13a/b): A solution of 270 mg (1.05 mmol) of 12a and 12b mixture andacetic acid (1.05 mmol, 0.061 mL) in 5 mL of dichloroethane was treatedwith NaBH(OAc)₃ under N2 atmosphere. The reaction was stirred at roomtemperature for 2 h. The reaction was quenched by adding 10% NaOH topH˜10. The mixture was extracted with ether (3×), washed with water andbrine. The organic phase was dried over Na₂SO₄ and concentrated underreduced pressure. Separation by chromatography (1%Et3N/EtOAc) gave 135mg (50%) of 13a and 60 mg (22%) of 13b as colorless oils. ¹H NMR (CDCl₃)of 8: δ 7.26 (m, 1H,), 6.94 (in, 2H), 6.70 (m, 1H), 3.80 (s, 3H),3.05-2.90 (m, 2H), 2.71 (m, 1H), 2.43 (s, 3H), 2.42-2.30 (m, 2H),2.28-2.15 (m,1H), 2.00-1.35 (in, 6H), 0.86 (d, 3H, J=8.25 Hz). ¹H NMR(CDCl₃) of 9: δ 7.23 (in, 1H,), 6.96 (m, 2H), 6.72 (m, 1H), 3.81 (s,3H),3.10-2.98 (m, 2H), 2.90 (m,1H), 2.75 (m, 1H), 2.50 (s, 3H), 2.47 (m,1H), 2.30-2.06 (m, 2H), 2.05-1.95 (m,2H), 1.90-1.50 (m, 4H), 0.75 (d,3H, J=8.56 Hz). ¹³C NMR (CDCl₃) of 8: 159.2, 152.0, 128.9, 118.0, 112.3,109.6, 59.7, 55.1, 51.1, 43.1, 42.5, 40.0, 38.3, 29.1, 25.6, 23.4, 14.8.Anal. Calcd for C1₇C₂₅NO: C, 78.72; H, 9.71; N, 5.40. Found: C, 78.79;H, 9.75; N, 5.34.

[0266](1S*,5R*,9R*)-2,9-Dimethyl-5-(m-hydroxyphenyl)-2-azabicyclo[3,3,1]nonane(14): Compound 13a was treated with 4 mL of glacial acetic acid and 4 mLof 48% aqueous hydrobromic acid at reflux temperature for 20 h. Thereaction was cooled to room temperature and diluted with 10 mL of water.The pH was adjusted to 10 by using 50% NaOH with ice cooling. Theproduct was extracted into a mixture of 3:1 1-butanol/toluene, driedover Na₂SO₄, and concentrated under reduced pressure. Separation bychromatography (½ CMA 80) provided 199 mg (84%) of 10 as a white solid.¹H NMR (CDCl₃) δ 7.15 (m, 1H,), 6.87-6.75 (m, 2H), 6.61 (m, 1H),3.10-2.90 (m, 2H), 2.77 (m, 1H), 2.44 (s, 3H), 2.50-2.30 (m, 2H),225-2.10 (m,1H), 2.00-1.60 (m, 5H), 1.60-1.40 (m, 1H), 0.80 (d, 3H,J=8.3 Hz). ¹³C NMR (CDCl₃) δ155.9, 1520, 129.1, 117.5, 113.0, 112.4,59.7, 51.0, 43.0, 42.0, 40.2, 38.0, 29.0, 25.6, 23.2, 14.6. Anal. Calcdfor C₁₆H₂₃NO.HCl: C, 68.19; H, 8.53; N, 4.97. Found: C, 68.25; H, 8.53;N, 5.03. The structure of this compound was determined by single crystalX-ray analysis.

[0267](1S*,5R*,9R*)-5-(m-Hydroxyphenyl)-9-methyl-2-azabicyclo[3,3,1]nonane(15): A solution of 200 mg (1.28 mmol) of phenyl chloroformate was addeddropwise to 300 mg (1.16 mmol) of 13a in 10 mL of dichloromethane atroom temperature under a nitrogen atmosphere. The reaction was refluxedfor 6 h. Since the reaction was not complete by TLC, the solvent wasthen changed to dichloroethane and the reflux was continued for another12 h. The mixture was cooled to room temperature and concentrated underreduced pressure. The resulting oil was treated with 10 mL of 1N NaOHand stirred with slight warming for 15 min. The product carbamate wasthen extracted with ether, and the ether layer was washed with 1N HCland water. The organic phase was dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was then treated with 5mL of ethanoland 1.5 mL of 50% aqueous KOH at reflux for 70 h. The mixture was cooledand concentrated under reduced pressure. The resulting concentrate wasextracted with ether (2×), and the ether layers were concentrated invaccuo. The resulting oil was dissolved into 10 mL of 1 N HCl and washedwith ether. The aqueous layer was then made strongly basic (pH>12) with50% NaOH with ice cooling. The desired amine 15 was extracted into ether(2×), and the ether extracts were washed, dried over Na₂SO₄, andconcentrated under reduced pressure to give 207 mg (70%) of crude 11 aslight yellow oil. The crude compound 15 was treated with 4 mL of glacialacetic acid and 4 mL of 48% aqueous hydrobromic acid at refluxtemperature for 20 h. The reaction was cooled to room temperature anddiluted with 10 mL of water. The pH was adjusted to 10 by using 50% NaOHwith ice cooling. The product was extracted into a mixture of 3:11-butanol/toluene, dried over Na₂SO₄, and concentrated under reducedpressure to yield 100 mg (51%) of 16 as a semi solid. The crude product16 was used directly in the next step without further purification. ¹HNMR (CD₃OD) δ 7.15 (m, 1H,), 6.79-6.75 (m, 2H), 6.65 (m, 1H), 3.70-3.30(m, 3H), 2.70 (m, 1H), 2.45-1.70 (m, 8H), 0.87 (d, 3H, J=8.3 Hz).

[0268](1S*,5R*,9R*)-5-(m-Hydroxyphenyl)-9-methyl-2-[(phenylmethyl)carbonyl]-2-azabicyclo[3,3,1]nonane(17): To a solution of 100 mg (0.43 mmol) of 16 and 190 mg (0.43 mmol)of BOP reagent and 0.19 mL (1.38 mmol) of triethylamine in 15 mL of THFwas added phenylacetic acid (70.25 mg, 0.52 mmol). The mixture wasstirred at room temperature for 1 h. The reaction was diluted with 10 mLof water and ether (10 mL). The aqueous layer was extracted with ether(2×). The combined ether layers were washed with NaHCO₃ and brine, anddried over Na₂SO₄. Evaporation of solvent provided the crude product 17as a colorless oil.(A spectrum of ¹H NMR was attached but the NMR datawas not interpreted here due to the rotamers).(1S*,5R*,9R*)-5-(m-Hydroxyphenyl)-9-methyl-2-(2′-phenylethyl)-2-azabicyclo[3,3,1]nonane(18): The crude amide 17 was dissolved in THF (8 mL). The solution wascooled to 0° C., and Borane:methyl sulfide complex (0.4 mL, 0.8 mmol)was added dropwise. After vigorous reaction ceased, the resultingmixture was slowly heated to reflux and maintained at that temperaturefor 4 h. The reaction mixture was cooled to 0° C., 6 mL of methanol wasadded, and the mixture was stirred for r 1 h. Anhydrous hydrogenchloride in ether (1 mL) was added to attain a pH<2, and the resultingmixture was gently refluxed for 1 h. After the mixture was cooled toroom temperature, methanol was added and the solvents were removed on arotovapor. The residue obtained was made basic (pH>12) by adding 25%NaOH and extracted with ether (3×). The combined ether layers were driedover Na₂SO₄ and concentrated under reduced pressure. Separation bychromatography (1% Et₃N/50% EtOAc/hexanes) gave 38 mg (71%) of amine 18as a colorless oil. ¹H NMR (CDCl₃) δ 7.30-7.14 (m, 6H), 6.85 (m, 2H),6.63 (m, 1H), 4.71 (br s, 1H), 3.05 (m, 2H), 2.88 (m, 1H), 2.79 (s, 4H),2.43-2.15 (m, 3H), 1.94-1.65 (m, 5H), 1.65-1.45 (m, 1H), 0.83 (d, 3H,J=8.2 Hz). ¹³C NMR (CDCl3) δ 155.7, 152.5, 140.9, 129.1, 128.8, 128.3,125.9, 117.7, 113.0, 112.4, 57.4, 57.2, 49.5, 42.4, 40.0, 38.7, 34.1,29.1, 26.2, 23.4, 14.7. Anal. Calcd for C₂₃H₂₉NO.HCl: Calcd: C, 74.27;H, 8.13; N, 3.77. Found: C, 74.16; H, 8.12; N, 3.71.

[0269](±)-(2,8a)-Dimethyl-4a-(3-Methoxyphenyl)-Octahydrobenzo[e]Isoquinoline(19): To a dry three neck round bottomed flask was charged 500 mg (2.3mmol) of 10 and 20 mL dry THF. This was cooled to −78° C. and to thiswas added 2.4 mL (3.12 mmol) s-BuLi (1.3M in cyclohexane) via a syringeover 5 minutes. The flask was then warmed to −20° C. and aged for 30min. The flask was then cooled to −78° C. and cannulated into a mixtureof 40 mL dry ethyl ether and 1.3 g (759 mmol) a,a′-dichloro xylene at−50° C. over 20 min. This was aged for 20 min. and then quench withice-cold 1N HCl. The contents of the flask were then transfered to aseparatory funnel with ice-cold ether and ice-cold 1N HCl. The aqueouslayer was removed and stored in an ice bath while the organic layer wastwice extracted with ice-cold 1N HCl. The combined aqueous layers wereplaced into a new separatory funnel and extracted twice with ice-coldethyl ether. The aqueous layer was then made basic with 50% NaOH atfirst and finally sat'd NaHCO₃ to pH 10. The aqueous layer was thenextracted 3 times with ice-cold ethyl ether and then discarded. Theether extracts were dried over K₂CO₃ and then filtered into a roundbottom flask and the solvent removed on the rotavap at 0° C. After allof the solvent was removed, the residue was dissolved in 40 mL seivedried CH₃CN and to this was added 870 mg NaI and 650 mg K₂CO₃. The flaskwas then attached to a reflux condenser and a heating mantle and thesystem heated under reflux for 3 hours. After this time, the flask wascooled to room temperature and filtered. The solvent was then removed ona rotavap and the residue dissolved in 40 mL punctillious ethanol. Tothis mixture was added 750 mg NaBH₄ in one portion and the mixtureallowed to stir overnight. On the following day, 1N HCl was added tothis mixture until no further evolution of hydrogen was observed. Thiswas stirred for 10 min and then 50% NaOH and water were added until themixure was clear and basic. The volatiles were then removed on a rotavapand the residue was extracted 3 times with 1:1 ethyl ether: ethylacetate. This was dried over K₂CO₃ and Na₂SO₄. After filtration andsolvent removal, a small portion of the crude residue was dissolved inCHCL₃ and spotted on a silica gel plate. Elution with 50% CMA-80 inCHCL₃ revealed a compound in the mixture that gave a pale spot whendipped in 5% PMA in EtOH at about 0.75 Rf. This is the 3° amine product.No other 3° amines were observed in the mixure. ¹H NMR of the crudemixture revealed the desired product as well as starting material 10 andother undesired products. Chromatography on silica gel using 12.5%CMA-80 in CHCL₃ gave the desired product in the early fractions justbehind the solvent front but not in the solvent front. This gave 115 mgof the desired product as a slightly yellow oil. Yield 15.5%.

[0270]¹H NMR (CDCl₃): δ 0.993 (s, 3H); 1.404 (ddd, 1H, J=13.7, 2.6, 2.6Hz); 2.149 (d, 1H, J=11.6 Hz); 2.229 (d, 1H, J=17.0 Hz); 2.240 (s, 3H);2.310 (dd, 1H, J=11.6, 1.5 Hz); 2.379 (ddd, 1H, J=12.1, 12.1, 3.2 Hz);2.646 (d, 1H, J=17.0 Hz); 2.862 (dd, 1H, J=13.7, 4.7 Hz); 2.885 (d, 1H,J=18.3 Hz); 2.962 (m, 1H); 3.570 (d, 1H, J=18.3 Hz); 3.634 (s, 3H);6.715 (ddd, 1H, J=8.1, 2.5, 0.9 Hz); 6.839 (m, 2H); 7.048 (d, 1H, J=7.6Hz); 7.197-7.080 (m, 4H).

[0271]¹³C NMR (CDCl₃): d 158.9, 148.9, 135.9, 135.6, 128.6, 128.36,128.0, 125.9, 125.5, 120.0, 113.9, 110.8, 64.04, 54.9, 52.2, 46.6, 40.6,40.11, 35.98, 31.5, 24.4.

[0272](±)-(2,8a)-Dimethyl-4a-(3-Hydroxyphenyl)-Octahydrobenzo[e]Isoquinoline(20): To a 10 mL single necked flask was added 100 mg (0.31 mmol) of(+)-(2,8a)-dimethyl-4a-(3-methoxyphenyl)-octahydrobenzo[e]isoquinolineand 0.8 mL of glacial acetic acid and 0.8 mL of 48% HBr. This mixturewas heated under reflux for 18 hours and then cooled to roomtemperature. The pH was then adjusted to 10 with cooling starting with50% NaOH and finishing with sat'd NaHCO₃. This was extracted 2 timeswith CHCl₃ and 2 times with 3:1 n-butanol:toluene. Both extracts weredried over K₂CO₃ and then the solvent was removed. The material fromboth extracts was examined by ¹H NMR and was shown to contain thedesired product. The material from the CHCl₃ layer was chromatographedon silica gel eluting with 25% CMA-80 in CHCl₃. This gave 27 mg of thedesired product 20 (28% yield). The residue was dissolved in MeOH and tothis was added 3 equivalents of 1N HCl in dry ethyl ether. The solventswere removed and several attempts were made to crystallize form ethylacetate/MeOH. This only provided an oil. The same result was obtainedwith ethyl ether/MeOH. Finally, ethyl acetate was added to the residueand warmed and the solvent removed on a rotavap. This process wasrepeated 5 times and the solid thus formed was placed on a high vacuumpump overnight. MP ° C. 270-275 (dec). C, H, N.

[0273]¹H NMR (DMSO): δ 1.014 (s, 3H); 1.587 (d, 1H, J=14.3 Hz); 2.072(s, 3H); 2.358 (d, 1H, J=17.4 Hz); 2.498 (d, 1H, J=17.4 Hz); 2.734 (s,3H); 2.924-2.792 (m, 3H); 3.113 (d, 1H, J=13.1 Hz); 3.602 (d, 1H,J=18.78 Hz); 6.562 (d, 1H, J=8.0 Hz); 6.611 (m, 2H); 6.993 (t, 1H, J=7.5Hz); 7.081 (d, 1H, J=7.5 Hz); 7.148 (t, 1H, J=7.8 Hz); 7.269-7.193 (m,2H); 9.30 (s, 1H); 9.898 (bs, 1H).

[0274]¹³C NMR (DMSO): δ 156.7, 146.4, 135.5, 133, 128.5, 128.4, 128.2,126.2, 125.7, 117.6, 114.3, 113.5, 59.2, 49.4, 38.6, 35.4, 35.2, 31.0,28.7, 22.8.

[0275] The butanol extracts contained 45 mg of the desired materialgiving an overall yield of 74.6%. TABLE 7 Radioligand Binding Results atall Three Opioid Receptors for New Antagonist Pharmacaphores IC₅₀ (nM ±SD) Compound # RTI # [³H] DAMGO^(a) [³H] DADLE^(b) [³H] U69, 593^(c)(14) 5989-30 243.7 ± 21.9  >10,000  1470 ± 28.4  (1.00 ± 0.08) (0.89 ±0.06) (18) 5989-31 4.54 ± 0.21 457.4 ± 50.5  27.2 ± 1.89 (1.08 ± 0.05)(0.88 ± 0.08) (1.25 ± 0.11) (21) 5989-28  406 ± 31.9 >10,000 306.4 ±28.4  (1.02 ± 0.07) (0.81 ± 0.06)

[0276] TABLE 8 IC₅₀ Data for New Antagonists Toward Reversal of AgonistStimulated GTP Binding IC₅₀ (nM ± SD) Compound # RTI # DAMGO^(a) SNC80^(b) U69, 593^(c) (14) 5989-30 288 ± 78  >1000 >1000 (18) 5989-31 5.96± 0.72 >1000 26.3 ± 8.3  (21) 5989-28 NA NA 1552 ± 164 

Example 4 κ-Selective N-Substituted Piperidines

[0277] Summary

[0278] The inhibition of radioligand binding and [³⁵S]GTPγS functionalassay data for N-methyl- andN-phenethyl-9β-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c) (FIG. 13)show that these compounds are pure antagonists at the μ, δ, and κ opioidreceptors. Since 5b and 5c have the 5-(3-hydroxyphenyl) group locked ina conformation comparable to an equatorial group of a piperidine chairconformation, this information provides very strong evidence that opioidantagonists can interact with opioid receptors in this conformation. Inaddition, it suggests that thetrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonistoperates via a phenyl equatorial piperidine chair conformation.

[0279] Chemistry

[0280] The synthesis of the N-methyl- andN-phenethyl-9β-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c,respectively) was achieved as illustrated in FIG. 13.¹ Treatment of1,2,6-trihydro-1,3-dimethyl-4-(3-methoxy)pyridine (6) with sec-butyllithium followed by quenching with allyl bromide provided the enamineadduct (7) which was cyclized without isolation to give2,9-dimethyl-5-(3-methoxyphenyl)-2-azabicyclo[3.3.1]non-3-ene (8a,b) ina 3:1 9β- to 9α-methyl ratio, using hydrochloric acid intetrahydrofuran. Reduction of unpurified 8a,b using sodium borohydridetriacetate followed by separation of the major isomer gave 9. Subjectionof 9 to O-demethylation using hydrobromic acid in acetic acid providedthe desired phenylmorphan (5b). Single crystal X-ray analysis showedthat 5b had the desired 9β-methyl relative configuration (FIG. 14). TheN-phenethyl derivative (5c) was prepared from intermediate 9. Treatmentof 9 with phenylchloroformate followed by hydrolysis of the resultingurethane with potassium hydroxide followed by O-demethylation withhydrobromic acid in acetic acid gave 10. Compound 10 was converted to 5cby coupling with phenyl acetic acid in the presence ofbenzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphatefollowed by borane reduction of the resulting amide intermediate.

[0281] Biological Results

[0282] Table 9 lists the radioligand binding data for compounds 5b and5c along with data for naltrexone. While the binding of 5b to all threeopioid receptors was weak, it is particularly interesting to note thatchanging the N-substituent from methyl to phenethyl (5c) provided adramatic increase in binding affinity, a feature shared by thecorresponding 4-(3-hydroxyphenyl)piperidine analogs (4a and 4b, Table10).² Furthermore, the relative binding affinities displayed by 5b and5c for mu and kappa opioid receptors are quite similar to that observedfor 4a and 4b. These results show that the binding affinities of 5b and5c are not adversely affected by the 1,5-carbon bridge present in thesestructures. In addition, it suggests a common binding mode for the twotypes of structures.

[0283] The increase in binding of [³⁵S]GTPγS stimulated by opioidagonists is an assay able to distinguish compounds of differing efficacyand intrinsic activity.³ The antagonist properties of test compounds canbe determined by measuring the inhibition of this stimulation To assesstheir potency as antagonists and to verify that 5b and 5c retain pureantagonist activity, the compounds were analyzed for either stimulationor inhibition of agonist stimulated GTP binding in comparison withnaltrexone (Table 11). In this functional assay, neither 5b nor 5cstimulated GTP binding as measured up to concentrations of 10 μM,showing that both compounds were devoid of agonist activity.⁴ Asmentioned previously, retention of pure antagonist activity regardlessof the N-substituent structure is a key feature that separates the3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonist fromoxymorphone-based antagonists which display pure antagonism only forcertain N-substituents such as the N-allyl or N-cyclopropylmethylderivatives. In their ability to reverse agonist-stimulated GTP binding,compound 5c displayed a higher potency than naltrexone. These resultsare striking since agonist activity in several opioid ligands isenhanced by N-substituents with two methylene groups terminated by aphenyl group (N-phenethyl). It is evident that the antagonist activityof 5c is due to factors different from those of the oxymorphone-typepure antagonists.

[0284] The data in Table 11 also demonstrates that the N-methyl toN-phenethyl change, 5b to 5c, results in a concomitant increase inantagonist potency. Thus, as is the case for the3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, the antagonist potency andnot the agonist/antagonist behavior of the9β-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c) is mediated by theN-substituent.

[0285] Discussion

[0286] These experiments demonstrated that N-methyl9β-methyl-5-(3-hydroxyphenyl)morphan (5b) is an opioid receptor pureantagonist. In addition, replacing the N-methyl with an N-phenethylgroup to give 5c resulted in a 63-, 60-, and 70-fold increase inantagonist potency at the mu, delta, and kappa opioid systems. Theseresults are particularly important since changing an N-methyl to anN-phenethyl substituent in all opioid systems which have the3-hydroxyphenyl group in an axial relationship relative to thepiperidine ring results in an increase in opioid agonist activity. Thisinformation strongly suggests that 5b and 5c are acting asconformationally rigid analogs of thetrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioidantagonists where the 3-hydroxyphenyl group is in an equatorial positionrelative to the piperidine ring.

[0287] In opioid alkaloids like naloxone (1a) and naltrexone (1b), the3-hydroxyphenyl ring is fixed in an axial orientation relative to thepiperidine ring by the rigid framework of the structure (FIG. 15). The3-hydroxyphenyl ring in the 3,4-dimethyl-4-(3-hydroxy phenyl)piperidineanalogs 4a can be either in axial or equatorial positions (FIG. 15). ¹Hand ¹³C NMR studies^(6,7) as well as molecular modeling studies² suggesta preference for the 3-hydroxyphenyl equatorial conformation.5-(3-Hydroxyphenyl)morphans like 5a-c are sterically constrained4-(3-hydroxyphenyl)piperidines with the 3-hydroxyphenyl ring fixed inthe equatorial position (FIG. 15). The pure antagonist activity of themorphans 5b and 5c strongly suggests that opioid ligands of the phenylpiperidine class express potent opioid antagonist activity with their3-hydroxyphenyl group in an equatorial position.

[0288] A comparison of the radioligand and [³⁵S]GTPγS binding propertiesof the N-substituted 9β-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c)to those of the N-substituted3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (4a and 4b) stronglysuggests that these two types of compounds are interacting with opioidreceptors in a similar mode. The pure antagonist activity of 5b, whichis increased when the N-methyl group is replaced by a phenethyl group togive 5c, properties unique to the3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonist, stronglysupports the hypothesis that this class of opioid antagonist expressespure antagonist activity with the 4-(3-hydroxyphenyl) group in anequatorial conformation.⁸

[0289] In summary, 9β-methyl-5-(3-hydroxyphenyl)morphans are a newstructural type of pure opioid antagonist. The data also stronglysupports the proposed 4-(3-hydroxyphenyl) equatorial piperidine chairmode of interaction for thetrans-3,4-dimethyl-(3-hydroxyphenyl)piperidine class of opioidantagonist.

[0290] Experimental Section

[0291] Melting points were determined on a Thomas-Hoover capillary tubeapparatus and are not corrected. Elemental analyses were obtained byAtlantic Microlabs, Inc. and are within ±0.4% of the calculated values.¹H-NMR were determined on a Bruker WM-250 spectrometer usingtetramethylsilane as an internal standard. Silica gel 60 (230-400 mesh)was used for all column chromatography. All reactions were followed bythin-layer chromatography using Whatman silica gel 60 TLC plates andwere visualized by UV or by charring using 5% phosphomolybdic acid inethanol. All solvents were reagent grade. Tetrahydrofuran and diethylether were dried over sodium benzophenone ketyl and distilled prior touse.

[0292] The [³H]DAMGO, DAMGO, and [³H][D-Ala²,D-Leu⁵]enkephalin wereobtained via the Research Technology Branch, NIDA, and were prepared byMultiple Peptide Systems (San Diego, Calif.). The [³H]U69,593 and[³⁵S]GTPγS (SA=1250 Ci/mmol) were obtained from DuPont New EnglandNuclear (Boston, Mass.). U69,593 was obtained from Research BiochemicalsInternational (Natick, Mass.). Levallorphan was a generous gift fromKenner Rice, Ph.D., NIDDK, NIH (Bethesda, Md.). GTPγS and GDP wereobtained from Sigma Chemical Company (St. Louis, Mo.). The sources ofother reagents are published.⁸

[0293]1,2,3,4-Tetrahydro-4-allyl-1,5-dimethyl-4-(3-methoxyphenyl)pyridine (7).To a solution of 500 mg (2.3 mmol) of1,2,6-trihydro-1,3-dimethyl-4-(3-methoxy)pyridine (6) in 15 mL of THF at−42° C. was added s-BuLi in cyclohexane (1.3M, 2.9 mmol). After 1 h,allyl bromide (2.3 mmol) was added, and the color of the solutionchanged from dark red to yellow. After been stirred for 1 h at −42° C.,the mixture was allowed to warmed to 0° C. and then quenched with water(10 mL). Diethyl ether (10 mL) was added, and the aqueous layer wasextracted with ether (2×). The combined ether layers were washed withwater (10 mL), saturated NaHCO₃, brine, and dried over Na2SO4.Evaporation of solvent afforded 590 mg (˜100%) of crude 7. The crudeproduct was used directly in the next step without further purification.¹H NMR (CDCl₃) δ 7.26 (m, 1H), 7.01 (m, 2H), 6.74 (m, 1H), 5.89 (s, 1H),5.82 (m, 1H), 5.13 (m, 2H), 3.80 (s, 3H), 2.68-2.40 (m, 3H), 2.55 (s,3H), 2.22 (m, 1H), 1.66 (m, 2H), 1.52 (s, 3H). ¹³C NMR (CDCl₃) δ 159.2,151.1, 136.7, 135.8, 128.7, 119.8, 117.4, 114.3, 110.1, 107.7, 55.1,46.1, 43.1, 43.0, 41.7, 36.4, 17.3.

[0294] 2,9-Dimethyl-5-(3-methoxyphenyl)-2-azabicyclo[3.3.1]non-3-ene(8ab). A solution of 300 mg (1.17 mmol) of 7 in 6 mL of 85% H₃PO₄/HCO2H(1:1) was stirred at room temperature for 72 h. The resulting dark-brownmixture was diluted with water (6 mL) and cooled in an ice bath whileNaOH (25% w/w) was added until pH 8. The aqueous solution was extractedwith CHCl₃ (3×). The combined organic layers were washed with aqueousNaHCO₃ and brine and dried over Na₂SO₄. Evaporation of the solvent gave270 mg (90%) of crude products 8a and 8b in a ratio of 3:1. The crudeproducts were used directly in the next step without furtherpurification. ¹H NMR (CDCl₃) of the mixture: δ 7.24-6.70 (m, 4H), 6.16(d, 1H, J=9.2 Hz), 4.34 (d, 1H, J=7.0 Hz), 4.13 (d, 1H, J=9.1 Hz), 3.80(s, 3H), 2.80 (s, 3H), 3.10-1.40 (m, 8H), 0.74 (d, 3H, J=8.6 Hz), 0.57(d, 3H, J=8.1 Hz).

[0295] 2,9β-Dimethyl-5-(3-methoxyphenyl)-2-azabicyclo[3.3.1]nonane (9).A solution of 270 mg (1.05 mmol) of 8a and 8b mixture and acetic acid(1.05 mmol, 0.061 mL) in 5 mL of dichloroethane was treated withNaBH(OAc)₃ under N₂ atmosphere. The reaction was stirred at roomtemperature for 2 h. The reaction was quenched by adding 10% NaOH topH˜10. The mixture was extracted with ether (3×), washed with water andbrine. The organic phase was dried over Na₂SO₄ and concentrated underreduced pressure. Isolation of the major isomer by chromatography (1%Et₃N/EtOAc) gave 135 mg (50%) of 9 as a colorless oil. ¹H NMR (CDCl₃) of9 δ 7.26 (m, 1H), 6.94 (m, 2H), 6.70 (m, 1H), 3.80 (s, 3H), 3.05-2.90(m, 2H), 2.71 (m, 1H), 2.43 (s, 3H), 2.42-2.30 (m, 2H), 2.28-2.15 (m,1H), 2.00-1.35 (m, 6H), 0.86 (d, 3H, J=8.25 Hz). ¹³C NMR (CDCl₃) of 9159.2, 152.0, 128.9, 118.0, 112.3, 109.6, 59.7, 55.1, 51.1, 43.1, 42.5,40.0, 38.3, 29.1, 25.6, 23.4, 14.8. Anal. (C₁₇H₂₅NO): C, H, N.

[0296] 2,9β-Dimethyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonane (5b).Compound 9 was treated with 4 mL of glacial acetic acid and 4 mL of 48%aqueous hydrobromic acid at reflux temperature for 20 h. The reactionwas cooled to room temperature and diluted with 10 mL of water. The pHwas adjusted to 10 by using 50% NaOH with ice cooling. The product wasextracted into a mixture of 3:1 1-butanol/toluene, dried over Na₂SO₄,and concentrated under reduced pressure. Separation by chromatography[50% (80% CHCl₃, 18% MeOH, 2% NH₄OH) in chloroform] provided 199 mg(84%) of 5b as a white solid. ¹H NMR (CDCl₃) δ 7.15 (m, 1H), 6.87-6.75(m, 2H), 6.61 (m, 1H), 3.10-2.90 (m, 2H), 2.77 (m, 1H), 2.44 (s, 3H),2.50-2.30 (m, 2H), 2.25-2.10 (m,1H), 2.00-1.60 (m, 5H), 1.60-1.40 (m,1H), 0.80 (d, 3H, J=8.3 Hz). ¹³C NMR (CDCl₃) δ 155.9. The hydrochloridesalt was prepared and crystallized from ether/methanol using 1N HCl inethyl ether. 152.0, 129.1, 117.5, 113.0, 112.4, 59.7, 51.0, 43.0, 42.0,40.2, 38.0, 29.0, 25.6, 23.2, 14.6. The structure of this compound wasdetermined by single crystal X-ray analysis. Anal. (C₁₆H₂₄ClNO): C, H,N.

[0297] 5-(3-Hydroxyphenyl)-9β-methyl-2-azabicyclo[3.3.1]nonane (10). Asolution of 200 mg (1.28 mmol) of phenyl chloroformate was addeddropwise to 300 mg (1.16 mmol) of 9 in 10 mL of dichloromethane at roomtemperature under a nitrogen atmosphere. The reaction was heated toreflux for 6 h. Since the reaction was not complete by TLC, the solventwas then changed to dichloroethane and the reflux was continued foranother 12 h. The mixture was cooled to room temperature andconcentrated under reduced pressure. The resulting oil was treated with10 mL of 1N NaOH and stirred with slight warming for 15 min. The productcarbamate was then extracted with ether, and the ether layer was washedwith 1N HCl and water. The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was then treated with 5mL of ethanol and 1.5 mL of 50% aqueous KOH at reflux for 70 h. Themixture was cooled and concentrated under reduced pressure. Theresulting concentrate was extracted with ether (2×), and the etherlayers were concentrated in vacuo. The resulting oil was dissolved into10 mL of 1 N HCl and washed with ether. The aqueous layer was then madestrongly basic (pH>12) with 50% NaOH with ice cooling. The desired aminewas extracted into ether (2×), and the ether extracts were washed, driedover Na₂SO₄, and concentrated under reduced pressure to give 207 mg(70%) of a light yellow oil. This was treated with 4 mL of glacialacetic acid and 4 mL of 48% aqueous hydrobromic acid at refluxtemperature for 20 h. The reaction was cooled to room temperature anddiluted with 10 mL of water. The pH was adjusted to 10 by using 50% NaOHwith ice cooling. The product was extracted into a mixture of 3:11-butanol/toluene, dried over Na₂SO₄, and concentrated under reducedpressure to yield 100 mg (51%) of 10 as a semisolid. The crude product10 was used directly in the next step without further purification. ¹HNMR (CD₃OD) δ 7.15 (m, 1H), 6.79-6.75 (m, 2H), 6.65 (m, 1H), 3.70-3.30(m, 3H), 2.70 (m, 1H), 2.45-1.70 (m, 8H), 0.87 (d, 3H, J=8.3 Hz).

[0298]5-(3-Hydroxyphenyl)-9β-methyl-2-(2′-phenylethyl)-2-azabicyclo[3.3.1]nonane(5c). To a solution of 100 mg (0.43 mmol) of 10 and 190 mg (0.43 mmol)of BOP reagent and 0.19 mL (1.38 mmol) of triethylamine in 15 mL of THFwas added phenylacetic acid (70.25 mg, 0.52 mmol). The mixture wasstirred at room temperature for 1 h. The reaction was diluted with 45 mLof water and ether (45 mL). The aqueous layer was extracted with ether(2×). The combined ether layers were washed with NaHCO₃ and brine, anddried over Na₂SO₄. Evaporation of solvent provided the crude product asa colorless oil. The crude amide was dissolved in THF (8 mL). Thesolution was cooled to 0° C., and borane:methyl sulfide complex (0.4 mL,0.8 mmol) was added dropwise. After vigorous reaction ceased, theresulting mixture was slowly heated to reflux and maintained at thattemperature for 4 h. The reaction mixture was cooled to 0° C., 6 mL ofmethanol was added, and the mixture was stirred for 1 h. Anhydroushydrogen chloride in ether (1 mL) was added to attain a pH<2, and theresulting mixture was gently refluxed for 1 h. After the mixture wascooled to room temperature, methanol was added, and the solvents wereremoved on a rotovap. The residue obtained was made basic (pH>12) byadding 25% NaOH and extracted with ether (3×). The combined ether layerswere dried over Na₂SO₄ and concentrated under reduced pressure.Separation by chromatography (1% Et₃N/50% EtOAc/hexanes) gave 38 mg(71%) of amine 5c as a colorless oil. ¹H NMR (CDCl₃) δ 7.30-7.14 (m,6H), 6.85 (m, 2H), 6.63 (m, 1H), 4.71 (br s, 1H), 3.05 (m, 2H), 2.88 (m,1H), 2.79 (s, 4H), 2.43-2.15 (m, 3H), 1.94-1.65 (m, 5H), 1.65-1.45 (m,1H), 0.83 (d, 3H, J=8.2 Hz). ¹³C NMR (CDCl₃) δ 155.7, 152.5, 140.9,129.1, 128.8, 128.3, 125.9. The hydrochloride salt was prepared andcrystallized from ether/methanol using 1N HCl in ethyl ether. 117.7,113.0, 112.4, 57.4, 57.2, 49.5, 42.4, 40.0, 38.7, 34.1, 29.1, 26.2,23.4, 14.7. Anal. (C₂₃H₃₀ClNO): C, H, N.

[0299] Opioid Binding Assays. Mu binding sites were labeled using[³H][D-Ala²-MePhe⁴,Gly-ol⁵]enkephalin ([³H]DAMGO) (2.0 nM, SA=45.5Ci/mmol), and delta binding sites were labeled using[³H][D-Ala²,D-Leu⁵]enkephalin (2.0 nM, SA=47.5 Ci/mmol) using rat brainmembranes prepared as described.⁹ Kappa-1 binding sites were labeledusing [³H]U69,593 (2.0 nM, SA=45.5 Ci/mmol) and guinea pig membranespretreated with BIT and FIT to deplete the mu and delta binding sites.⁸

[0300] [³H]DAMGO binding proceeded as follows: 12×75 mm polystyrene testtubes were prefilled with 100 μL of the test drug which was diluted inbinding buffer (BB: 10 mM Tris-HCl, pH 7.4, containing 1 mg/mL BSA),followed by 50 μL of BB, and 100 μL of [³H]DAMGO in a protease inhibitorcocktail (10 mM Tris-HCl, pH 7.4, which contained bacitracin (1 mg/mL),bestatin (100 μg/mL), leupeptin (40 μg/mL), and chymostatin (20 μg/mL).Incubations were initiated by the addition of 750 μL of the preparedmembrane preparation containing 0.2 mg/mL of protein and proceeded for 4to 6 h at 25° C. The ligand was displaced by 10 concentrations of testdrug, in triplicate, 2×. Nonspecific binding was determined using 20 μMlevallorphan. Under these conditions, the K_(d) of [³H]DAMGO binding was4.35 nM. Brandel cell harvesters were used to filter the samples overWhatman GF/B filters, which were presoaked in wash-buffer (ice-cold 10mM Tris-HCl, pH 7.4).

[0301] [³H][D-Ala²,D-Leu⁵]enkephalin binding proceeded as follows: 12×75mm polystyrene test tubes were prefilled with 100 mL of the test drugwhich was diluted in BB, followed by 100 μL of a salt solutioncontaining choline chloride (1 M, final concentration of 100 mM), MnC₁₂(30 mM, final concentration of 3.0 mM), and, to block mu sites, DAMGO(1000 nM, final concentration of 100 nM), followed by 50 μL of[³H][D-Ala²,D-Leu⁵]enkephalin in the protease inhibitor cocktail.Incubations were initiated by the addition of 750 μL of the preparedmembrane preparation containing 0.41 mg/mL of protein and proceeded for4 to 6 h at 25° C. The ligand was displaced by 10 concentrations of testdrug, in triplicate, 2×. Nonspecific binding was determined using 20 μMlevallorphan. Under these conditions the K_(d) of[³H][D-Ala²,D-Leu⁵]enkephalin binding was 2.95 nM. Brandel cellharvesters were used to filter the samples over Whatman GF/B filters,which were presoaked in wash buffer (ice-cold 10 mM Tris-HCl, pH 7.4).

[0302] [³H]U69,593 binding proceeded as follows: 12×75 mm polystyrenetest tubes were prefilled with 100 μL of the test drug which was dilutedin BB, followed by 50 μL of BB, followed by 100 μL of [³H]U69,593 in thestandard protease inhibitor cocktail with the addition of captopril (1mg/mL in 0.1N acetic acid containing 10 mM 2-mercapto-ethanol to give afinal concentration of 1 μg/mL). Incubations were initiated by theaddition of 750 μL of the prepared membrane preparation containing 0.4mg/mL of protein and proceeded for 4 to 6 h at 25° C. The ligand wasdisplaced by 10 concentrations of test drug, in triplicate, 2×.Nonspecific binding was determined using 1 μM U69,593. Under theseconditions the K_(d) of [³H]U69,593 binding was 3.75 nM. Brandel cellharvesters were used to filter the samples over Whatman GF/B filters,which were presoaked in wash buffer (ice-cold 10 mM Tris-HCl, pH 7.4)containing 1% PEI.

[0303] For all three assays, the filtration step proceeded as follows: 4mL of the wash buffer was added to the tubes, rapidly filtered and wasfollowed by two additional wash cycles. The tritium retained on thefilters was counted, after an overnight extraction into ICN Cytoscintcocktail, in a Taurus beta counter at 44% efficiency.

[0304] [³⁵S]-GTPγS Binding Assay. Ten frozen guinea pig brains (HarlanBioproducts for Science, Inc, Indianapolis, Ind.) were thawed, and thecaudate putamen were dissected and homogenized in buffer A (3mL/caudate) (Buffer A=10 mM Tris-HCl, pH 7.4 at 4° C. containing 4 μg/mLleupeptin, 2 μg/mL chymostatin, 10 μg/mL bestatin, and 100 gg/mLbacitracin) using a polytron (Brinkian) at setting 6 until a uniformsuspension was achieved. The homogenate was centrifuged at 30,000×g for10 min at 4° C. and the supernatant discarded. The membrane pellets werewashed by resuspension and centrifugation twice more with fresh bufferA, aliquotted into microfuge tubes, and centrifuged in a Tomyrefrigerated microfuge (model MTX 150) at maximum speed for 10 min. Thesupernatants were discarded, and the pellets were stored at −80° C.until assayed.

[0305] For the [³⁵S]GTPγS binding assay, all drug dilutions were made upin buffer B [50 mM TRIS-HCl, pH 7.7/0.1% BSA]. Briefly, 12×75 mmpolystyrene test tubes received the following additions: (a) 50 μLbuffer B with or without an agonist, (b) 50 μL buffer B with or without60 μM GTPγS for nonspecific binding, (c) 50 μL buffer B with or withoutan antagonist, (d) 50 μL salt solution which contained in buffer B 0.3nM [³⁵S]GTPγS, 600 mM NaCl, 600 μM GDP, 6 mM dithiothreitol, 30 mMMgCl₂, and 6 mM EDTA, and (e) 100 μL membranes in buffer B to give afinal concentration of 10 μg per tube. The final concentration of thereagents were 100 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, 1 mM dithiothreitol,100 μM GDP, 0.1% BSA, 0.05-0.1 nM [³⁵S]GTPγS, 500 nM or 10 μM agonists,and varying concentrations (at least 10 different concentrations) ofantagonists. The reaction was initiated by the addition of membranes andterminated after 4 h by addition of 3 mL ice-cold (4° C.) purified water(Milli-Q uv-Plus, Millipore) followed by rapid vacuum filtration throughWhatman GF/B filters presoaked in purified water. The filters were thenwashed once with 5 mL ice-cold water. Bound radioactivity was counted byliquid scintillation spectroscopy using a Taurus (Micromedic) liquidscintillation counter at 98% efficiency after an overnight extraction in5 mL Cytoscint scintillation fluid. Nonspecific binding was determinedin the presence of 10 μM GTPγS. Assays were performed in triplicate, andeach experiment was performed at least 3×.

[0306] Data Analysis. The data of the two separate experiments (opioidbinding assays) or three experiments ([³⁵S]-GTPγS assay) were pooled andfit, using the nonlinear least-squares curve-fitting language MLAB-PC(Civilized Software, Bethesda, Md.), to the two-parameter logisticequation¹⁰ for the best-fit estimates of the IC₅₀ and slope factor. TheK_(i) values were then determined using the equation:IC₅₀/1+([L]/K_(d)).

[0307] Single-Crystal X-Ray Analysis of 5b. Crystals of 5b were grownfrom ethyl ether/methanol. Data were collected on a computer-controlledautomatic diffractometer, Siemens P4, with a graphite monochromator onthe incident beam. Data were corrected for Lorentz and polarizationeffects, and a face-indexed absorption correction was applied. Thestructure was solved by direct methods with the aid of program SHELXS¹¹and refined by full-matrix least-squares on F2 values using programSHELXL.¹¹ The parameters refined included the coordinates andanisotropic thermal parameters for all nonhydrogen atoms. Hydrogen atomson carbons were included using a riding model in which the coordinateshifts of their covalently bonded atoms were applied to the attachedhyrdogens with C—H=0.96 Å. H angles were idealized and Uiso(H) set atfixed ratios of Uiso values of bonded atoms. Coordinates were refinedfor H atoms bonded to nitrogen and oxygen. Additional experimental andstructural analysis including an ORTEP figure, tables of atomiccoordinates, bond lengths, and angles are available as supplementarymaterial. Atomic coordinates are also available from the CambridgeCrystallographic Data Centre (Cambridge University Chemical Laboratory,Cambridge CB2 1EW, UK).

REFERENCES

[0308] (1) Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zimmerman, D. M.;Robey, R. L. Application of metalated enamines to alkaloid synthesis. Anexpedient approach to the synthesis of morphine-based analgesics. J. Am.Chem. Soc. 1980, 102, 5955-5956. WARNING: read the backgroundinformation relating to analogs of MPTP including refferences forZimmerman et al., J. Med. Chem. 1986, 29, 1517-1520 and references citedin reference 2.

[0309] (2) Zimmerman, D. M.; Leander, J. D.; Cantrell, B. E.; Reel, J.K.; Snoddy, J.; Mendelsohn, L. G.; Johnson, B. G.; Mitch, C. H.Structure-activity relationships of thetrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine antagonists for μ and κopioid receptors. J. Med. Chem. 1993, 36(20), 2833-2841.

[0310] (3) Thomas, J. B.; Mascarella, S. W.; Rothnman, R. B.; Partilla,J. S.; Xu, H.; McCullough, K. B.; Dersch, C. M.; Cantrell, B. E.;Zimmerman, D. M.; Carroll, F. I. Investigation of the N-substituentconformation governing potency and μ receptor subtype-selectivity in(+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists.J. Med. Chem. 1998, 41(11), 1980-1990.

[0311] (4) Xu, H.; Lu, Y. -F.; Partilla, J. S.; Brine, G. A.; Carroll,F. I.; Rice, K. C.; Lai, J.; Porreca, F.; Rothman, R. B. Opioid peptidereceptor studies. 6. The 3-methylfentanyl congeners RTI-4614-4 and itsenantiomers differ in efficacy, potency, and intrinsic efficacy asmeasured by stimulation of [³⁵S]GTP-γ-S binding using cloned μ-opioidreceptors. Analgesia 1997, 3, 3542.

[0312] (5) Aldrich, J. V. Analgesics. In Burger's Medicinal Chemistryand Drug Discovery, Wolff, M. E. Eds.; John Wiley & Sons, Inc.: 1996;Vol. 3: Therapeutic Agents.

[0313] (6) Casy, A. F.; Dewar, G. H.; Al-Deeb, O. A. A. Stereochemicalinfluences upon the opioid ligand activities of 4-alkyl-4-arylpiperidinederivatives. Chirality 1989, 1, 202-208.

[0314] (7) Casy, A. F.; Dewar, G. H.; Al-Deeb, O. A. A. Stereochemicalstudies of the 4-alkyl-4-arylpiperidine class of opioid ligand. Magn.Reson. Chem. 1989, 27, 964-972.

[0315] (8) Rothmnan, R. B.; Bykov, V.; de Costa, B. R.; Jacobson, A. E.;Rice, K. C.; Brady, L. S. Interaction of endogenous opioid peptides andother drugs with four kappa opioid binding sites in guinea pig brain.Peptides 1990, 11, 311-331.

[0316] (9) Rothman, R. B.; Xu, H.; Seggel, M.; Jacobson, A. E.; Rice, K.C.; Brine, G. A.; Carroll, F. I. RTI-4614-4: an analog of(+)-cis-3-methylfentanyl with a 27,000-fold binding selectivity for muversus delta opioid binding sites. Life Sci. 1991, 48, PL111-PL-116.

[0317] (10) Rodbard, D.; Lenox, R. H.; Wray, H. L.; Ramseth, D.Statistical characterization of the random errors in theradioimmunoassay dose-response variable. Clin. Chem. 1976, 22, 350-358.

[0318] (11) SHELXTL-Plus, Release 5.03, Sheldrick, G. M., SiemensAnalytical X-ray Instruments, Inc., Madison, Wis., 1995. TABLE 9Radioligand Binding Results at the Mu, Delta, and Kappa Opioid Receptorsfor N-Methyl- and N-Phenethyl-9β-methyl-5-(3-hydroxyphenyl)morphans Ki(nM ± SD) μ δ κ Compd [³H]DAMGO^(a) [³H]DADLE^(b) [³H]U69,593^(c) 5b 166± 15  >10,000 816 ± 66  5c 3.11 ± 0.21 272 ± 30  14.5 ± 0.99 1b,naltrexone 1.39 ± 0.40  949 ± 6.6  4.71 ± 0.7 

[0319] TABLE 10 Affinities of the N-Substituted-3,4-dimethyl-(3′-hydroxyphenyl)piperidine Antagonists for the Mu and Kappa OpioidReceptors^(a) Ki (nM) μ κ Compd [³H]Nal^(b) [³H]EKC^(c) 4a 80 833 4b 1.552 1b, naltrexone 0.56 3.9

[0320] TABLE 11 Inhibition by Antagonists of [³⁵S]GTPγS Binding inGuinea Pig Caudate Stimulated by DAMGO (mu), SNC80 (delta), and U69,593(kappa) Selective Opioid Agonists^(a) Ki (nM ± SD) μ δ κ Compd(DAMGO)^(a) (SNC80)^(b) (U69,593)^(c) 5b 21.2 ± 2.30  750 ± 85.9  105 ±10.9 5c 0.338 ± 0.028 12.6 ± 1.01  1.34 ± 0.084 1b, naltrexone 0.930 ±0.21  19.3 ± 2.25 2.05 ± 0.21

[0321]

[0322] This Example is described in Thomas et al, J. Med. Chem., V. 41,No. 21, 4143-4149 (1998) incorporated herein by reference, inclusive ofthe “Supporting Information Available” described at p. 4149.

Example 5 Synthesis of 9β-methyl-2-alkyl-7-oxo-5-arylmorphans

[0323] Summary

[0324] A convergent synthetic approach to9β-methyl-2-alkyl-7-oxo-5-arylmorphans has been developed utilizingalkylation of the metalloenaimine of1,2,3,6-tetrahydro-4-aryl-1-alkylpyridines with2-(chloromethyl)-3,5-dioxahex-1-ene (Okahara's reagent).

[0325] Chemistry

[0326] Thus, treatment of the lithium salt of 15a with 18 provided 16a(not isolated) which cyclized on acidification with hydrochloric acid intetrahydrofuran to give a 10:1 mixture of 17a and 17d as determined by¹H NMR analysis (FIG. 16). Separation by silica gel chromatographyprovided 43% of 17a. Proton assignments were made using a combination ofHMQC, HMBC, and COSY. The 9β stereochemical assigrnents for 17a weremade using NOESY techniques. In particular, the axial 9β-methyl groupwas observed to show an NOE interaction with the 4D proton.¹

[0327] To expand this method to the ring unsubstituted derivatives andto explore potential limitations of the chemistry, compounds 17b (47%)and 17c (42%) were also prepared. It was shown earlier that differencesin reactivities exist between unsubstituted and substituted systems,15b, c and 15a. For example, s-BuLi is needed to effectively deprotonate15a as opposed to 15b and 15c which require only n-BuLi.² This is aconvenient route to the 7-oxo-phenylmorphan derivatives from eithersubstituted or unsubstituted 4-phenyl-1,2,3,6-tetra-hydropyridines fromintermediates which can be prepared in bulk and stored for long periodsof time.

[0328] In summary, the 9β-methyl-7-oxo-5-arylmorphan 17a can be preparedin a convergent manner from tetrahydropyridine 15a by alkylation with2-(chloromethyl)-3,5-dioxahex-1-ene 18 followed by cyclization underacidic conditions. This method provides the first reported access to the9β-methyl substituted system with good control of the stereochemistry.Application of the method to 15b and 15c provides a higher yieldingroute to the unsubstituted 7-oxo-phenylmorphan ring system and isamenable to large-scale synthesis.

REFERENCES AND NOTES

[0329] 1. ¹H NMR (CDCl₃) δ 0.92 (d, 3H, 9-CH₃), 1.76 (d, 1H, H4β), 2.23(dd, 1H, H8), 2.33 (s,3H, NCH₃), 2.37 (dd, 1H, H4p), 2.38 (dd, 1H, H3),2.43 (d, 1H, H6), 2.50 (q, 1H, H9), 2.62 (d, 1H, H6), 2.72 (m, 1H, H3),2.97 (d, 1H, H8), 3.10 (m, 1H, HI), 3.78 (s, 3H, OCH₃), 6.75 (dd, 1H,ArH), 6.87 (s, 1H, ArI1), 6.92 (d, 1H, ArH), 7.25 (dd, 1H, ArH).

[0330] 2. Barnett, C. J.; Copley-Merriman, C. R.; Maki, J. J. Org. Chem.1989, 54, 4795-4800.

[0331] Supplementary Information

[0332] Melting points were determined on a Thomas-Hoover capillary tubeapparatus and are not corrected. Elemental analyses were obtained byAtlantic Microlabs, Inc. and are within ±0.4% of the calculated values.¹H-NMR spectra were determined on a Bruker WM-250 spectrometer usingtetramethylsilane as an internal standard. Radial chromatography wasperformed on a Harrison Research Chromatron model 7924T. All reactionswere followed by thin-layer chromatography using Whatman silica gel 60TLC plates and were visualized by UV or by charring using 5%phosphomolybdic acid in ethanol or by iodine staining. All solvents werereagent grade. In reactions, tetrahydrofliran and diethyl ether weredried over sodium benzophenone ketyl and distilled prior to use.

[0333] Note: The choice of piperidone in this synthesis is important inorder to avoid the production of neurotoxic tetrahydropyridines such as1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It has beendemonstrated that the neurotoxic properties associated with MPTP orm-methoxy-MPTP are eliminated by any one of the following:N-substituents larger than methyl, piperidine ring substitution, and/oraryl substituents larger than methoxy.¹⁻³

[0334] 2,9-Dimethyl-5-(3-methoxyphenyl)-2-azabicyclo[3.3.1]nonan-7-one(17a): To a solution of 1500 mg (6.9 mmol) of tetrahydropyridine 15a⁴and TMEDA (2.1 mL, 13.8 mmol) in 30 mL of THF at −42° C. was addeds-BuLi in cyclohexane (1.3 M, 8.9 mmol). After 1 h,2-(chloromethyl)-3,5-dioxa-1-hexene 18 (1.32 g, 9.7 mmol) was added, andthe color of the solution changed slowly from dark red to yellow. Afterbeing stirred for 1 h at 42° C. and kept 3 h at −23° C., the mixture wasallowed to warm to 0° C. and then quenched with 1N HCl (20 mL). Diethylether (20 mL) was added, and the aqueous layer was extracted with ether(2×). The aqueous layer was adjusted to pH 10 and extracted with diethylether (3×). The combined ether layers were washed with water (10 mL),saturated NaHCO₃, brine, and dried over Na₂SO₄. Evaporation of solventafforded 1.31 g (−60%) of crude 16a. The crude product was used directlyin the next step without further purification. ¹H NMR (CDCl₃) δ 7.27 (t,1H, J=9.6 Hz), 7.02 (m, 2H), 6.72 (m, 1H), 5.83 (s, 1H), 4.93 (s, 2H),3.81 (s, 3H), 3.43 (s, 3H), 2.70-2.40 (m, 8H), 2.52 (s, 3H), 1.61 (s,3H). A solution of 500 mg of 16a in 3 mL of 6 M HCl and 25 mL of THF wasstirred at room temperature for 72 h. The resulting brown mixture wasneutralized with 10% NaOH (10 mL) until pH>9. The aqueous solution wasextracted with diethyl ether (3×). The combined organic layers werewashed with aqueous NaHCO₃ and brine. The organic phase was dried overNa₂SO₄ and concentrated under reduced pressure. The NMR shows that theratio of 17a to 17d is about 10:1. Separation by chromatography [10%(80% chloroform, 18% methanol, 2% NH₄OH)/chloroform] gave 310 mg of 17aas a colorless oil (43% from 15a). ¹H NMR (CDCl₃) δ 7.28 (t, 1H, J=9.5Hz), 6.93 (m, 1H), 6.86 (m, 1H), 6.76 (dd, 1H, J=2.2, 9.7 Hz), 3.81 (s,3H), 3.13 (m, 1H), 3.0 (d, 1H, J=20.5 Hz), 2.76 (m, 1H), 2.66-2.17 (m,6H), 2.36 (s, 3H), 1.76 (m, 1H), 0.93 (d, 3H, J=8.2 Hz). ¹³C NMR (CDCl₃)210.5, 159.6, 148.7, 129.4, 117.6, 112.2, 110.3, 61.7, 55.9, 55.0, 47.1,42.8, 41.4, 39.6, 29.5, 13.8. Anal. Calcd. for C₁₇H₂₃NO₂: Found: C,76.72; H, 8.62, N, 5.23.

[0335] 2-Ethyl-5-(3-methoxyphenyl)-2-azabicyclo[3.3.1]nonan-7-one (17b):To a solution of 500 mg (2.3 mmol) of tetrahydropyridine 15b [1] andtetramethylethylene diamine (TMEDA) (0.69 mL, 4.6 mmol) in 15 mL of THFat −42° C. was added n-BuLi in hexanes (2.5M, 2.9 mmol). After 1 h,2-(chloromethyl)-3,5-dioxa-1-hexene 18 (440 mg, 3.2 mmol) was added, andthe color of the solution changed slowly from dark red to yellow. Afterbeing stirred for 1 h at −42° C. and kept 3 h at −23° C., the mixturewas allowed to warm to 0° C. and then quenched with 1N HCl (10 mL).Diethyl ether (10 mL) was added, and the aqueous layer was extractedwith ether (2×). The aqueous layer was adjusted to pH 10 and extractedwith diethyl ether (3×). The combined ether layers were washed withwater (10 mL), saturated NaHCO₃, brine, and dried over Na₂SO₄.Evaporation of solvent afforded 510 mg (70%) of crude 16b. The crudeproduct was used directly in the next step without further purification.¹H NMR (CDCl₃) δ 7.20 (t, 1H, J=9.1 Hz), 6.97 (m, 2H), 6.67 (dd, 1H,J=1.9, 8.4 Hz), 6.03 (d, 1H, J=9.8 Hz), 4.74 (s, 2H), 4.69 (d, 1H, J=9.6Hz), 3.79 (s, 3H), 3.26 (s, 3H), 2.86 (q, 2H, J=8.6 Hz), 2.80-2.39 (m,6H), 2.12 (m, 2H), 1.02 (t, 3H, J=8.6 Hz). A solution of 510 mg of 16bin 3 mL of 6 M HCl and 25 mL of THF was stirred at room temperature for72 h. The resulting brown mixture was neutralized with 10% NaOH (10 mL)until pH>9. The aqueous solution was extracted with diethyl ether (3×).The combined organic layers were washed with aqueous NaHCO₃ and brine.The organic phase was dried over Na₂SO₄ and concentrated under reducedpressure. Separation by chromatography [10% (80% chloroform, 18%methanol, 2% NH₄OH)/chloroform] gave 352 mg (80%, 47% from 15b) of 17bas colorless oil. ¹H NMR (CDCl₃) δ 7.28 (t, 1H, J=9.6 Hz), 6.92 (m, 2H),6.78 (dd, 1H, J=3.0, 9.7 Hz), 3.81 (s, 3H), 3.60 (m, 1H), 2.82 (m, 3H),2.55 (q, 2H, J=8.6 Hz), 2.44-1.92 (m, 7H), 1.10 (t, 3H, J=8.6 Hz). ¹³CNMR (CDCl₃) 209.4, 158.7, 149.0, 128.5, 115.9, 110.2, 10.0, 54.1, 52.4,52.2, 47.4, 44.4, 38.2, 37.6, 37.1, 36.7, 12.7. Anal. Calcd. forC₁₇H₂₃NO₂: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.78; H, 8.60; N,5.24.

[0336] 2-Benzyl-5-(3-methoxyphenyl)-2-azabicyclo[3.3.1]nonan-7-one(17c): 3-Bromoanisole (50.0 g, 0.264 mol) was dissolved in 150 mL of THFand then chilled to −78° C. n-Butyllithium (1.6M, 175 mL, 0.276 mol) wasthen added while maintaining the reaction temperature at −70° C. orbelow. After complete addition, the reaction mixture was stirred for anadditional 60 min. 1-Benzyl-4-piperidone in 150 mL of THF was then addedat such a rate as to maintain the reaction temperature at −70° C. orbelow. The reaction was stirred at −70° C. for an additional 15 min,then the dry ice-acetone bath was removed, and the reaction was allowedto come to room temperature. Brine (400 mL) was added, and the organiclayer was separated and washed with an additional 300 mL of brine. Theorganic layer was separated, dried (K₂CO₃), and concentrated in vacuo.6N HCl (250 mL) was added to the oily residue which was then washed withEtOAc. The aqueous layer was separated, basified with 50% NaOH, andextracted with EtOAc. The EtOAc layer was separated, dried (K₂CO₃), andconcentrated in vacuo to give 75.7 g of4-(3-methoxyphenyl)-1-benzyl-4-piperidinol as an orange oil. A samplewas chromatographed on silica gel using hexane/EtOAc (7:3) mixtures asthe eluent to afford a yellow oil which was dissolved in ether andtreated with ethereal hydrochloric acid to give4-(3-methoxyphenyl)-1-benzyl-4-piperidinol hydrochloride as a whitesolid (mp 195-197° C.). ¹H NMR (CDCl₃) (free base) δ (ppm) 1.64-1.75 (m,2H), 2.09-2.21 (m, 2H), 2.41-2.51 (m, 2H), 2.71-2.80 (m, 2H), 3.51 (s,2H), 3.80 (s, 3H), 6.77-6.81 (m, 1H), 7.06-7.09 (m, 2H), 7.23-7.35 (m,6H). Anal. Calcd for C₁₉H₂₃NO₂ HCl.½H₂O: C, 66.56; H, 7.06; N, 4.09.Found: C, 66.41; H, 7.31; N, 4.33.

[0337] This material, 4-(3-methoxyphenyl)-1-benzyl-4-piperidinol (75.7g, 0.25 mol), was dissolved in 400 mL of toluene, tosic acid (101.4 g,0.53 mol) was added, and the mixture was heated under reflux in a DeanStark trap for 90 min. The reaction mixture was cooled to roomtemperature, and water (400 mL) was added. The bottom layers wereseparated, made basic with 5N NaOH, and extracted with EtOAc. The EtOAclayer was separated, washed with brine, dried (K₂CO₃), and concentratedin vacuo to give 73.0 g of a red-orange oil. The oil was chromatographedon silica gel using hexane/EtOAc (4:1) mixtures as the eluent to afford54.2 g of 1,2,3,6-tetrahydro-4-(3-methoxyphenyl)-1-benzylpyridine 15c(78%) as an orange oil. A sample of the free base was converted to itshydrochloride salt (ethereal HCl) to give1,2,3,6-tetrahydro-4-(3-methoxyphenyl)-1-benzylpyridine hydrochloride asa white solid (mp 196-196° C.). ¹H NMR (CDCl₃) (free base) δ (ppm)2.54-2.57 (br m, 2H), 2.68-2.73 (m, 2H), 3.14-3.18 (m, 2H), 3.63 (s,2H), 3.78 (s, 3H), 6.04-6.07 (m, 1H), 6.79 (dd, 1H), 6.91-7.00 (m, 2H),7.19-7.39 (m, 6H). Anal. Calcd. for C₁₉H₂₁NO.HCl.¼H₂O: C, 71.46; H,6.79; N, 4.39. Found: C, 71.63; H, 6.97; N, 4.42.

[0338] 1,2,3,6-Tetrahydro-4-(3-methoxyphenyl)-1-benzylpyridine 15c (5.0g, 0.018 mol) was dissolved in 70 mL of THF and chilled to −78° C. in adry ice-acetone bath. N-Butyllithium (1.6M, 12.0 mL, 0.0193 mol) wasadded to the reaction mixture at a rate that would maintain thetemperature at −70° C. or below. After complete addition, the reactionwas stirred for an additional 15 min, and the dry ice bath was replacedwith a salt-ice bath. When the temperature rose to −15° C.,2-(chloromethyl)-3,5-dioxahex-1-ene 18 (3.2 g, 0.023 mol) in 40 mL ofTHF was added while keeping the reaction temperature at −10° C. or belowand stirring for an additional 15 min at −15° C. The bath was removed,and the reaction was stirred at room temperature for an additional 17 h.The reaction was quenched with 30 mL of brine, the organic layer wasseparated, washed with 2×100 mL of brine, separated, dried (K₂CO₃), andconcentrated in vacuo to get 6.8 g of an orange oil. This was dissolvedin 100 mL of THF, and 20 mL of 6N HCl was added. This reaction wasstirred at room temperature overnight. The reaction mixture wasneutralized with aqueous NaHCO₃, added 100 mL of EtOAc, and separatedthe organic layer. The organic layer was washed with 10% NaHCO₃, brine,then separated, dried (K₂CO₃), and concentrated in vacuo to give 4.8 gof 17c as a red oil. The oil was chromatographed on silica gel usinghexane/EtOAc (65:35) mixtures, as the eluent, to yield an oil whichcrystallized upon addition of ether to give 2.5 g (42%) of5-(3-methoxyphenyl)-2-benzyl-2-azabicyclo[3.3.1]nonan-7-one 17c as abeige solid (mp 108-109° C.). ¹H NMR (CDCl₃) δ (ppm) 1.88-1.91 (m, 2H),2.12-2.21 (m, 2H), 2.31-2.49 (m, 3H), 2.75-2.99 (m, 3H), 3.49 (br m,1H), 3.60-3.72 (q, 2H), 3.80 (s, 3H), 6.75-6.80 (m, 1H), 6.88-6.96 (m,2H), 7.25-7.34 (m, 6H). ¹³C NMR (CDCl₃) δ 210.4, 159.8, 150.2, 138.7,129.5, 128.6, 128.3, 127.0, 117.0, 111.3, 111.0, 59.0, 55.2, 53.7, 53.3,45.5, 39.2, 38.7, 38.0, 37.7. Anal. Calcd. for C₂₂H₂₅NO₂: C, 78.77; H,7.51; N, 4.18. Found: C, 78.76; H, 7.59; N, 4.20.

REFERENCES

[0339] [1] Zimmerman D M, Cantrell B E, Reel J K, Hemrick-Luecke S K,Fuller R W. J. Med. Chem. 1986;29:1517-1520.

[0340] [2] Fuller R W. 1986.

[0341] [3] Fries D S, de Vries J, Hazelhoff B, Horn A S. J. Med. Chem.1986;29:424.

[0342] [4] Barnett C J, Copley-Merriman C R, Maki J. J. Org. Chem.1989;54:47954800.

[0343] This Example is described in Thomas et al, Tetrahedron Letters,V. 39, 7001-7004 (1998), incorporated herein by reference.

Example 6 Selective Delta Opioid Receptor Agonists

[0344] Chemistry

[0345] Preparation of 3a,b began with reductive amination of1,3-dimethyl-4-piperidone with aniline using titanium (IV) isopropoxide¹which gave 5a,b as a mixture of cis and trans diastereomers in 75% yieldin a ratio of 70:30 (FIG. 17). These were separated by columnchromatography and carried forward independently. These intermediateswere then coupled to the butylated hydroxyanisole (BHA) ester of4-fluorobenzoic acid to give (6a,b) in 91% and 68% yields.² Removal ofthe BHA group was accomplished by transesterification with refluxingsodium methoxide in toluene/N-methylpyrrolidinone followed bysaponification of the methyl ester. The zwitterionic intermediates wereisolated as HCl salts and converted directly into diethylamides usingbenzotriazol-1-yl-oxy-tris-(dimethylamino) phosphoniurnhexafluorophosphate (BOP a.k.a. Castro's reagent), diethylamine, andtriethylamine in a tetrahydrofuran (THF) slurry to give 7a and 7b in 90%and 59% yields, respectively. Conversion to the N-allyl group wasaccomplished by treating 7a,b with phenyl chloroformate followed byhydrolysis of the resulting carbamates with potassium hydroxide inisopropyl alcohol. N-Alkylation with allyl bromide then gave 3a,b in 40%and 20% yield, respectively. Stereochemical assignments for 3a were madeusing NOESY spectra and vicinal coupling constants. Proton and carbonassignments were made using a combination of COSY and HETCORR spectra. Alarge coupling constant (J=13.0 Hz) between H5 and H4 indicated adiaxial arrangement between these protons showing that the 4-diarylamineis in the equatorial position. The NOESY spectrum contained a stronginteraction between 5H-axial and the 3-methyl showing that the methylgroup is also axial. The axial equatorial relationship between themethyl and the 4-diarylamine group established the cis relativestereochemistry for 3a.

[0346] Biological Activity

[0347] The binding affinities of the compounds for the μ, δ, and κopioid receptors were determined using competitive binding assaysfollowing previously reported procedures.³ The results are listed inTable 12.

[0348] Results and Discussion

[0349] The radioligand binding data for the compounds 3a,b along withcomparative data for BW373U86 (1) and the two enantiomers ofcis-3-methylfentanyl 4 are shown in Table 12. Compound 3a (the cisisomer) is more potent and more selective for the δ opioid receptorrelative to both the μ and κ opioid receptors than 3b (the transisomer). This difference in selectivity is due to a significantly loweraffinity of the trans isomer for the 6 receptor relative to the μ or κopioid receptors. The 11.9 nM Ki values for 3a combined with the 1212 nMKi value at the μ receptor compare favorably to the Ki values for 1(BW373U86) particularly when one considers that 3a is racemic and doesnot possess all the structural features present in 1, namely the3′-hydroxy group on the aromatic ring and a methyl group comparable tothe piperazine 2-methyl group.

[0350] A comparison of the binding data of 3a to that ofcis-3-methylfentanyl, particularly the more potent 3R,4S-isomer 4b, iseven more striking than the comparison of 3a to 1. Compound 4b gave a3900-fold selectivity for the μ receptor relative to the δ receptor,whereas 3a possesses a 102-fold δ selectivity relative to the μreceptor. This results from a sevenfold increase in affinity at the δreceptor (11.9 nM vs. 77.3 nM) and a >60,000-fold loss in affinity atthe μ receptor. Thus changing the propanamido and phenethyl groupspresent in 4b to the 4-diethylcarboamidophenyl and allyl in 3a convertsa highly μ-selective fentanyl analog to a δ-selective ligand. It ishighly likely that the gain in δ-receptor potency is due to the changeof the propanamido group of 4 to the diethylcarboxamidophenyl group in3a. The loss is preceptor potency may be due to both changes. Regardlessof the reason for the δ opioid receptor selectivity, compound 3arepresents a novel ligand for the δ opioid receptor.

REFERENCES

[0351] (1) Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. Animproved method for reductive alkylation of amines using titanium(IV)isopropoxide and sodium cyanoborohydride. J. Org. Chem. 1990, 55,2552-2554.

[0352] (2) Hattori, T.; Satoh, T.; Miyano, S. Convenient synthesis oftriarylamines via ester-mediated nucleophilic aromatic substitution.Synthesis 1995, 514-518.

[0353] (3) Thomas, J. B.; Zheng, X.; Mascarella, S. W.; Rothman, R. B.;Dersch, C. M.; Partilla, J. S.; Flippen-Anderson, J. L.; George, C. F.;Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. N-Substituted9β-methyl-5-(3-hydroxyphenyl)morphans are opioid receptor pureantagonists. J. Med. Chem. 1998, 41(21), 4143-4149.

[0354] (4) Xu, H.; Kim, C. -H.; Zhu, Y. C.; Weber, R. J.; Rice, K. C.;Rothman, R. B. (+)-cis-Methylfentanyl and its analogs bindpseudoirreversibly to the mu opioid binding site: Evidence forpseudoallostenrc modulation. Neuropharmacology 1991, 30, 455-462. TABLE12 Radioligand Binding Results at the μ, δ, and κ Opioid Receptors for(±)-4-[(N-Allyl-3-methyl-4-piperidinyl)-phenylamino]N,N-diethylbenzamides Ki (nM ± SD) μ δ κCompd [3H]DAMGO^(a) [3H]DADLE^(b) [3H]U69,593^(c) μ/δ 1,  36 ± 3.4 0.91± 0.05 NA 40 BW373U86 3a, (±)-cis- 1212 ± 132  11.9 ± 0.9  3284 ± 299 102 isomer 3b, (±)-trans- 1589 ± 86  126 ± 5  8695 ± 978  13 isomer 4a,(3S,4R)- 30.6 ± 5.13 >1000 NA 0.03 isomer^(d) 4b, (3R,4S)- 0.020 ± 0.00577.3 ± 6.7  57.4 ± 6.1  0.0003 isomer^(d)

[0355] TABLE 13 Elemental Analyses % Calculated % Found Melting pointCompound (C %, H %, N %) (C %, H %, N %) ° C. 7a 66.42, 8.36, 9.6866.20, 8.31, 9.76 193-194 7b 65.73, 8.39, 9.58 65.69, 8.33, 9.62 199-2013a 69.93, 8.24, 9.41 70.06, 8.30, 9.10   221-225.5 3b 69.93, 8.24, 9.4169.66, 8.31, 9.31 177-178

[0356] Experimental

[0357] (±)-(3RS,4SR)-4-Phenylamino-1,3-dimethylpiperidine (5a) and(±)-(2RS,3RS)-4-phenylamino-1,3-dimethylpiperidine (5b)

[0358] 1,3-Dimethyl-4-piperidone (11.77 g, 92.68 mmol), aniline (8.5 mL,93.4 mmol), and titanium isopropoxide (35 mL, 117.7 mmol) were heated at55° C. for 20 h under a nitrogen atmosphere. The reaction mixture wasallowed to cool and diluted with ethanol (100 mL). Sodium borohydride(5.0 g, 131.6 mmol) was then added, and the reduction was allowed toproceed at room temperature for 4 h. The reaction was quenched byaddition of water, filtered over celite, and the filtrate was washedwith ethanol. After evaporation of the solvent under reduced pressure,the white residue was taken up in ethyl acetate and again filtered overcelite. After evaporation of the solvent under reduced pressure andchromatography on silica gel using ethyl acetate in hexanes (20:80), a70:30 mixture of diastereomers (5a and 5b) (13.80 g, 73%) was obtained.Further separation by chromatography using the same system affordedfirst 5a (8.46 g) as a yellow oil, tentatively assigned a cis relativestereochemistry, and then 5b (2.04 g) as a white solid. 1H NMR 5a(CDCl₃) δ 0.98 (d, 3H, J=6.9 Hz), 1.67±1.89 (m, 2H), 2.03-2.58 (m, 4H),2.18 (s, 3H), 3.41±3.68 (m, 2H), 6.60 (dd, 2H, J=0.9 Hz, J=8.6 Hz), 6.67(dd, 1H, J=0.9 Hz, J=7.3 Hz), 7.15 (t, 2H, J=7.3 Hz). 1H NMR 5b (CDCl₃)δ 0.98 (d, 3H, J=6.3 Hz), 1.19-1.48 (m, 1H), 1.58-1.62 (m, 1H), 1.77 (t,1H, J=11.0 Hz), 1.96-2.15 (m, 2H), 2.27 (s, 3H), 2.78-2.93 (m, 3H),3.27-3.41 (m, 1H), 6.57 (dd, 2H, J=1.0 Hz, J=8.6 Hz), 6.66 (dd, 1H,J=1.0 Hz, J=7.3 Hz), 7.12 (t, 2H, J=7.3 Hz).

[0359](±)-2,6-Di-tert-butyl-4-methoxyphenyl-4-[N-[(3RS,4SR)-N,3-dimethyl-4-piperidinyl)phenylamino]benzoate (6a)

[0360] (±)-(3RS,4SR)-4-Phenylamino-1,3-dimethylpiperidine (5a) (3.41 g,16.72 mmol) was dissolved in dry tetrahydrofuran (THF, 13 mL) and dryhexamethylphosphoramide (HMPA, 5 mL), and cooled to −42° C. A 2.5 Msolution of n-butyllithium in hexanes (7.7 mL, 19.25 mol) was slowlyadded, and the reaction mixture was kept at 0° C. for 1 h. The reactionmixture was cannulated into a solution of(2,6-di-tert-butyl-4-methoxyphenyl)-4-fluorobenzoate (6.0 g, 16.76 mmol)in dry THF (13 mL) and dry HMPA (5 mL) at room temperature then heatedto 45-50° C. for 5 h. The reaction mixture was cooled then quenched witha solution of NH₄Cl and diluted with ether. The aqueous layer was madebasic (pH=14) with NaOH 25%, extracted with ether (200 mL), and theethereal layer was washed with water three times. After drying withMgSO₄ and evaporation of the solvents under reduced pressure, a crudebrown oil was afforded. Chromatography on silica gel using ethyl acetatein hexanes (20:80) gave 6a (8.20 g, 91%) as a yellow solid: 1H NMR(CDCl₃) δ 1.21 (d, 3H, J=6.9 Hz), 1.31 (s, 18H), 1.53-1.71 (m, 2H),1.89-1.97 (m, 1H), 2.04 (s, 3H), 2.03-2.32 (m, 1H), 2.59-2.88 (m, 3H),3.81 (s, 3H), 4.00-4.06 (m, 1H), 6.58 (d, 2H, J=9.1 Hz), 6.89 (s, 2H),7.22 (d, 2H, J=8.2 Hz), 7.33 (d, 2H, J=7.2 Hz), 7.41 (t, 1H, J=7.2 Hz),7.97 (d, 2H, J=9.0 Hz).

[0361](±)-2,6-Di-tert-butyl-4-methoxyphenyl-4-[N-{(3RS,4RS)-N,3-dimethyl-4-piperidinyl}phenylamino]benzoate(6b)

[0362] (±)-(2RS,3RS)-4-Phenylamino-1,3-dimethylpiperidine (5b) (2.65 g,12.99 mmol) was treated with a 2.5 M solution of n-butyllithium inhexanes (6 mL, 15 mol) in dry THF (10 mL) and dry HMPA (4 mL) andcoupled with (2,6-di-tert-butyl-4-methoxyphenyl)-4-fluorobenzoate (4.65g, 12.99 mmol) in dry THF (10 mL) and dry HMPA (4 mL) as before.Purification afforded 6b (4.80 g, 68%) as a yellow solid: 1H NMR (CDCl₃)δ 1.07 (d, 3H, J=5.6 Hz), 1.31 (s, 18H), 1.63-2.15 (m, 5H), 2.25 (s,3H), 2.85-2.97 (m, 2H), 3.68-3.78 (m, 1H), 3.81 (s, 3H), 6.63 (d, 2H,J=9.1 Hz), 6.88 (s, 2H), 7.19 (d, 2H, J=7.1 Hz), 7.33 (t, 1H, J=7.1 Hz),7.44 (t, 2H, J=7.7 Hz), 7.95 (d, 2H, J=9.1 Hz).

[0363](±)-4-[N-{(3RS,4SR)-N,3-Dimethyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamide(7a)

[0364](±)-2,6-Di-tert-butyl-4-methoxyphenyl-4-[N-{(3RS,4SR)-N,3-dimethyl-4-piperidinyl}phenylamino]benzoate(6a) (6.5 g, 11.99 mmol) in toluene (150 mL) and N-methylpyrrolidinone(MP, 40 mL) was added to freshly prepared sodium methoxide (120 mmol)and heated at reflux for 4 h. After evaporation of the toluene underreduced pressure, the residue was dissolved in a mixture of MeOH and H₂O(12:1, 150 mL) and heated at reflux for 1 h. After evaporation of thealcohol, the residue was taken up in water (400 mL) and extracted withhexanes (2×100 mL). The aqueous layer was made acidic (pH=1) with 10%HCl, saturated with NaCl, and extracted with a mixture of CH₂Cl₂ and THF(3:1, 5′200 mL). After drying over Na₂SO₄, the solvents were evaporatedunder reduced pressure. This was then treated with diethylamine (1.2mL), benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphoniumhexafluorophosphate (BOP a.k.a. Castro's reagent) (5.0 g, 11.31 mmol)),and triethylamine (4.2 mL) in THF (100 mL) for 30 min. The reactionmixture was next diluted with ether (300 mL), washed with water (2×75mL), saturated NaHCO₃ (75 mL), and dried over Na₂SO₄ providing a blackoil following evaporation of the solvents under reduced pressure.Chromatography on silica gel using hexanes/ethylacetate/ethanol/triethylamine (60:40:2:2) afforded 7a (4.10 g, 90%) as ayellow liquid. This was converted to the hydrochloride salt using 1N HClin ether. ¹H NMR (CD₃OD) δ 1.07-1.38 (m, 12H), 1.42±1.61 (m, 1H),1.68-1.92 (m, 1H), 2.86 (s, 3H), 3.03±3.21 (m, 1H), 3.27±3.60 (m, 6H),4.30±4.48 (m, 1H), 6.80 (d, 2H, J=8.3 Hz), 7.14 (d, 2H, J=7.7 Hz), 7.26(t, 3H, J=7.5 Hz), 7.40 (t, 2H, J=7.4 Hz); ¹³C NMR (CD₃OD) δ 12.2, 25.6,30.4, 44.5, 55.7, 56.0, 60.2, 119.4, 127.4, 128.8, 130.7, 130.8, 146.1,150.8, 173.8. Anal. (C₂₄H₃₄ClN₃O.H₂O): C, H, N.

[0365](±)-4-[N-{(3RS,4RS)-N,3-Dimethyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamide(7b)

[0366](±)-2,6-Di-tert-butyl-4-methoxyphenyl-4-[N-{(3RS,4RS)-N,3-dimethyl-4-piperidinyl}phenylamino]benzoate(6b) (7.38 g, 13.62 mmol) was transesterified with sodium methoxide (135mmol) in toluene (150 mL) and NMP (40 mL) and then hydrolyzed with MeOHand H₂O (12:1, 165 mL) as before. The resulting acid was dissolved inTHF (200 mL) with triethylamine (5 mL), diethylamine (2 m]L), and BOPreagent (6.1 g, 13.80 mmol) as above. Work-up and chromatography onsilica gel as above afforded 7b (3.02 g, 59%) as a yellow liquid.Conversion to the hydrochloride salt was done with 1 N HCl in ether. ¹HNMR (CD₃OD) δ 1.10-1.25 (m, 12H), 1.76-2.28 (s, 3H), 2.99 (t, 1H, J=12.5Hz), 3.12-3.29 (m, 1H), 3.31-3.58 (m, 7H), 4.12-4.29 (m, 1H), 6.78 (d,2H, J=8.8 Hz), 7.18 (d, 2H, J=7.3 Hz), 7.22 (d, 2H, J=8.8 Hz), 7.33 (t,1H, J=7.4 Hz), 7.48 (t, 2H, J=7.5 Hz); ¹³C NMR (CD₃OD) δ 16.1, 29.0,35.3, 43.8, 55.3, 58.7, 60.7, 116.9, 127.3, 127.8, 129.1, 130.7, 131.2,144.0, 152.0, 173.9. Anal. (C₂₄H₃₄ClN₃O.25H₂O): C, H, N.

[0367](±)-4-[N-{(3RS,4SR)-N-Allyl-3-methyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamide(3a).

[0368](±)-4-[N-{(3RS,4SR)-N,3-Dimethyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamide(7a) (4.1 g, 10.82 mmol) was treated with phenyl chloroformate (1.25 mL,11.13 mmol) in 1,2-dichloroethane (35 mL) at room temperature for 24 h.The reaction was quenched with water and NaOH 30% then extracted withCHCl₃. After drying over Na₂SO₄ and evaporation of the solvents underreduced pressure, the crude product was chromatographed on silica gel togive a mixture of starting material and product which was then treatedwith methanol (100 mL), water (60 mL), isopropanol (50 mL), and NaOH 50%(30 mL) at reflux for 5 h. The alcohols were evaporated under reducedpressure, and the aqueous layer was extracted with CHCl₃/THF (3:1).After drying with Na₂SO₄, the solvents were evaporated under reducedpressure. Chromatography on silica gel using hexanes/ethylacetate/ethanol/triethylamine (50:50:3:3) afforded starting material(6a), (548 mg, 13%), as a yellow oil followed by the N-demethylatedmaterial (924 mg, 30%) as a yellow oil using ethanol/triethylamine(80:20) as eluent. The latter material was dissolved in ethanol (40 mL)and treated with allyl bromide (220 μL, 2.54 mmol) and K₂CO₃ (1.0 g,7.24 mmol) at room temperature for 24 h. After evaporation of theethanol under reduced pressure, the residue was chromatographed onsilica gel using hexanes/ethyl acetate/ethanol/triethylamine (50:50:3:3)to give 3a (950 mg, 93%) as a yellow oil. This was converted to thehydrochloride as previously described: ¹H NMR (δ₄-MeOH) 1.18 (m, 6H),1.23 (d, 3H, J=7.4 Hz), 1.54 (d, 1H, J=13.0 Hz), 1.81 (ddd, 1H, J=13.0Hz, 13.0 Hz, 11.0 Hz), 2.91 (m, 1H), 3.09 (dd, 1H, J=13.0 Hz, 13.0 Hz),3.44 (m, 7H), 3.75 (d, 1H, 7.4 Hz), 4.38 (d, 1H, J=13.5 Hz), 5.59 (d,1H, J=9.9 Hz), 5.60 (d, 1H, J=17.0 Hz), 6.00 (ddd, 1H, J=17.0 Hz, 17.0Hz, 7.4 Hz), 6.79 (d, 2H, J=8.5 Hz), 7.14 (d, 2H J=8.0 Hz), 7.23 (d, 2H,J=8.5 Hz), 7.28 (dd, 1H, J=8.0 Hz, 8.0 Hz), 7.40 (dd, 2H, J=8.0 Hz, 8.0Hz). ¹³C NMR (d4-MeOH) 11.3, 13.2 (broad), 24.5, 29.3, 45.0 (broad),52.4, 55.2, 56.7, 59.6, 118.3, 125.9, 126.4, 126.6, 127.7, 129.7, 145.0,149.8, 172.7. Anal. (C₂₆H₃₆ClN₃O..25H₂O): C, H, N.

[0369](±)-4-[N-{(3RS,4RS)-N-Allyl-3-methyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamide(3b).

[0370](±)-4-[N-{(3RS,4RS)-N,3-Dimethyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamide(7b) (502 mg, 1.32 mmol) was treated with phenyl chloroformate (170 μL,1.51 mmol) in 1,2-dichloroethane (4 mL) at room temperature for 24 h.The product was worked-up as above, and chromatography on silica gelusing hexanes/ethyl acetate/ethanol/triethylamine (75:25:1:1) affordedfirst the phenylcarbamate as a white solid followed by the startingmaterial (117 mg, 23%) as a yellow liquid. The carbamate was treatedwith methanol (20 mL), water (15 mL), isopropanol (10 mL), and NaOH 50%(5 mL) and worked-up as above to give the crude N-demthylatedintermediate as a yellow oil. This was dissolved in ethanol (5 mL) andtreated with allyl bromide (100 μL, 1.15 mmol) and K₂CO₃ (500 mg, 3.62mmol) for 16 h at room temperature. Work-up and purification as aboveafforded 3b (70 mg, 15% overall) as a yellow oil. This was converted tothe hydrochloride salt as previously described: ¹H NMR (CD₃OD) δ1.10-1.26 (m, 9H), 1.741.96 (m, 1H), 1.98-2.29 (m, 2H), 2.88-3.01 (m,1H), 3.10-3.22 (m, 1H), 3.35-3.61 (m, 7H), 3.73 (d, 2H, J=7.3 Hz), 4.20(dt, 1H, J=3.4 Hz, J=11.5 Hz), 5.55 (s, 1H), 5.61 (d, 1H, J=5.4 Hz),5.85-6.03 (m, 1H), 6.78 (d, 2H, J=8.8 Hz), 7.19 (d, 2H, J=7.8 Hz), 7.23(d, 2H, J=8.8 Hz), 7.34 (t, 1H, J=7.4 Hz), 7.51 (t, 2H, J=7.6 Hz); ¹³CNMR (CD₃OD) δ 11.9, 13.9, 16.2, 28.9, 35.2, 52.9, 58.3, 59.1, 60.1,117.0, 126.8, 127.6, 127.8, 129.0, 130.7, 131.2, 144.1, 151.8, 173.9.Anal. (C₂₆H₃₆ClN₃O.0.25H₂O): C, H, N.

Example 7 N-alkyl-4β-methyl-5-phenylmorphans

[0371] Summary

[0372] A convergent, highly stereoselective synthetic approach toN-alkyl-4β-methyl-5-phenylmorphans has been developed utilizingalkylation of the metalloenamine ofN-alkyl-1,2,3,6-tetrahydro-4-phenylpyridines with2-(chloromethyl)-3,5-dioxahex-1-ene (Okahara's reagent) followed byClemmensen reduction.

[0373] Chemistry

[0374] 4β-methyl-(3-hydroxyphenyl)morphans were stereoselectivelysynthesized as shown in FIG. 18. Alkylation of 8¹ with2-(chloromethyl)-3,5-dioxohex-1-ene (Okahara's reagent)² followed byhydrolysis of the methoxymethyl protecting group (FIG. 18) gives enamine12. In the alkylation reaction, the methyl group apparently exerts apowerful directing effect since enamine 12 is the sole product.Cyclization under acidic conditions occurs regiospecifically on carbon 1(phenylmorphan numbering) due to the specific migration of the doublebond during the alkylation reaction. Furthermore, since the oxidationstate of carbon 7 does not change following cyclization, no hydrideshift occurs and the stereogenic center of carbon 4 is preservedproviding 2,4β-dimethyl-7-oxo-5-(3-methoxyphenyl)morphan (13) as asingle diastereomer. Clemmensen reduction³ and deprotection of thephenol⁴ then completes the synthesis of2,4β-dimethyl-5-(3-hydroxyphenyl)morphan (3, R═CH₃) in 48% overall yieldfrom 8. The stereochemical assignments for 3 (R═CH₃) were made usingNOESY spectra of a sealed degassed sample obtained with mixing time of1.500 sec and an interpulse delay of 4 sec.⁵ A strong interactionbetween the 4-methyl group and the 9β and 3β protons established the4β-stereochemistry.

[0375] A requirement for significant quantities of 3 and its analogs forin vivo testing coupled with the usefulness of intermediates similar to13 in the preparation of delta opioid receptor selective agonists,^(6,7)suggested improving the overall yield of the alkylation/cyclizationsequence. Experimentation with a variety of conditions revealed thataddition of the metalloenamine of 8 to a solution of Okahara's reagent,rather than the reverse, gave much higher yields in the metalloenaminealkylation. In combination with an extractive workup to removeformaldehyde (formed by hydrolysis of the methoxymethyl group) andcyclization conditions similar to those defined by Bonjoch et al.,⁸ theoverall yield of the alkylation/cyclization sequence for 13 wassignificantly improved (75% for this work vs. 30% using the one-potprocedure).⁹

[0376] In summary, this example provides a highly diastereoselectivesynthetic approach to the N-alkyl-4β-methyl-5-(3-hydroxyphenyl)morphansystem as well as providing a higher yielding route to the useful7-oxo-5-(3-methoxyphenyl)morphan opioid intermediates.

REFERENCES AND NOTES

[0377] 1. Wemer, J. A.; Cerbone, L. R.; Frank, S. A.; Ward, J. A.;Labib, P.; Tharp-Taylor, R. W.; Ryan, C. W. J. Org. Chem. 1996, 61,587-597.

[0378] 2. Gu, X. -P.; Nishida, N.; Ikeda, I.; Okahara, M. J. Org. Chem.1987, 52, 3192-3196.

[0379] 3. Bosch, J.; Bonjoch, J. Heterocycles 1980, 14, 505.

[0380] 4. Rice, K. C. J. Med. Chem. 1977, 20, 164165.

[0381] 5. Proton assignments for 3 were made using a combination of COSYand HETCORR spectra. ¹H NMR (d4-MeOH) δ 0.782 (d, 3H, J=7.5 Hz), 1.65(m, 1H), 1.78 (m, 1H), 1.85 (m, 1H), 2.02 (d, 1H, J=15 Hz), 2.08 (m,1H), 2.24 (m, 1H), 2.29 (m, 1H), 2.46 (q, 1H, J=7.5 Hz), 2.54 (d, 1H,J=15.0 Hz), 2.92 (s, 3H), 3.26 (d, 1H, J=13.6 Hz), 3.70 (m, 1H), 3.86(dd, 1H, J=13.6 Hz, 5.3 Hz), 6.67 (m, 1H), 7.15 (t, 3H, J=7.9 Hz).

[0382] 6. Bertha, C. M.; Flippen-Anderson, J. L.; Rothman, R. B.;Porreca, F.; Davis, P.; Xu, H.; Becketts, K.; Cha, X. -Y.; Rice, K. C.J. Med. Chem. 1995, 38, 1523-1537.

[0383] 7. Bertha, C. M.; Ellis, M.; Flippen-Anderson, J. L.; Porreca,F.; Rothman, R. B.; Davis, P.; Xu, H.; Becketts, K.; Rice, K. C. J. Med.Chem. 1996, 39, 2081-2086.

[0384] 8. Bonjoch, J.; Casamitjana, N.; Gracia, J.; Bosch, J.Tetrahedron Lett. 1989, 30, 5655-5658.

[0385] 9. General Procedure for Alkylation/Cyclization Sequence:(CAUTION: Read reference 4 and references cited therein for informationon N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP and itsderivatives.) The appropriate tetrahydropyridine derivative (1 eq) isdissolved in THF (20 mL/g) and cooled to −10° C. n-Butyl lithium (1.6Min hexanes) is slowly added until a red color is maintained followed byan addition of 1.1 eq. This material is stirred for 1 h at −10° C. andthen cannulated quickly into a solution of Okahara's reagent (distilledto high purity) in THF (15 mL/g, 1.1 eq) at −78° C. followed by stirringfor 2 h. The temperature should be kept below −30° C. duringcannulation. This material is then poured into 2N HCl and extractedtwice with ethyl ether. The aqueous layer is allowed to stand for 15 minfollowed by addition of 50% NaOH to pH 14 and extraction (3×) with ethylether. The ether is then washed (1N NaOH, H₂O) and the solvent removedunder vacuum. The resulting residue of product and water is dissolved inMeOH (30 mL/g) and nitrogen is bubbled through the solution for 5 min.To this is added concentrated HCl (2 mL/g), and the mixture is allowedto stand at room temperature until the reaction is complete as indicatedby TLC (up to 7 days). TLC condition: SiO₂; elution with 50% (80%CHCl₃:18% CH₃OH:2% NH₄OH) in CHCl₃. Detection: 5% phosphomolybdic acidin ethanol. All compounds gave satisfactory ¹H and ¹³C NMR and massspectra.

[0386] This Example is described in Thomas et al, Tetrahedron Letters,Vol. 40, pp. 403-406 (1999), incorporated herein by reference.

[0387] Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

[0388] All references cited above are incorporated into this applicationby reference in their entirety unless noted otherwise.

What is claimed as new and is desired to be secured by Letters Patent ofthe United States is:
 1. A compound represented by formula (I):

wherein R₁ is hydrogen, an alkyl group, an aryl group, or an aralkylgroup; R₂ is hydrogen, an alkyl group, an aryl group, or an alkarylgroup; and R₃ is

each X is, independently, halogen, —OH, —OR, an all group, an arylgroup, —NH₂, —NHR, —N(R)₂, —CF₃, —CN or —C(O)NH₂, —C(O)NHR, or—C(O)N(R)₂; each R is, independently, an alkyl group, an aryl group oran alkaryl group, wherein when X is —N(R)₂ the R groups may, together,form a cyclic alkyl group; n is 0 or an integer from 1 to 5; and R_(a)is hydrogen or an alkyl group, or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein R₁ is hydrogen, a C₁₋₄alkyl group, a phenyl group, or an aralkyl group; R₂ is hydrogen or aC₁₋₄ alkyl group; and n is 0, 1, 2, 3 or
 4. 3. The compound of claim 2,wherein R₁ is hydrogen or a C₁₋₄ alkyl group; and n is 0, 1, 2, 3 or 4.4. The compound of claim 3, wherein R₁ is hydrogen or a C₁₋₃ alkylgroup; R₂ is hydrogen or a methyl group; n is 1, 2, or 3, and at leastone X is —OH, —OCH₃ or —F.
 5. The compound of claim 4, wherein at leastone X is —OH.
 6. A compound represented by formula (II):

R₁ is an alkyl group or aralkyl group; and R₃, R₄, R₅, R₆ are each,independently, hydrogen, an alkyl group, —OH, —NHK, —NHR, —N(R)₂,halogen, —OR, —CF₃, —CN, —NO₂, or —NHC(O)R, wherein when any of R₃, R₄,R₅, or R₆ is N(R)₂ the R groups may, together, form a cyclic alkylgroup; each R is, independently, an alkyl group, an aryl group, or analkaryl group; and R₇ is hydrogen or an alkyl group, or apharmaceutically acceptable salt thereof.
 7. The compound of claim 6,wherein R₁ is a C₁₋₈ alkyl group or an aryl-C₁₋₄ alkyl group; at mostthree of R₃, R₄, R₅, R₆ are each, independently, an alkyl group, —OH,—NH₂, —NHR, —N(R)₂, halogen, —OR, —CF₃, —CN, —NO₂, or —NHC(O)R; and R₇is hydrogen or a C₁₋₈ alkyl group.
 8. The compound of claim 7, whereinR₁ is a C₁₋₈ alkyl group or a phenyl-C₁₋₄ alkyl group; at most two ofR₃, R₄, R₅, and R₆ are each, independently, an alkyl group, —OH, —NH₂,—NHR, —N(R)₂, halogen, —OR, —CF₃, —CN, —NO₂, or —NHC(O)R; R₇ is a C₁₋₈alkyl group.
 9. The compound of claim 8, wherein R₁ is a C₁₋₄ alkylgroup or an aryl-C₁₋₃ alkyl group; one of R₃, R₄, R₅, or R₆ is an alkylgroup, —OH, —NH₂, —NHR, —N(R)₂, halogen, —OR, —CF₃, —CN, —NO₂, or—NHC(O)R; and R₇ is a C₁₋₄ alkyl group.
 10. The compound of claim 9,wherein R₃, R₄, R₅, and R₆ are hydrogen.
 11. A compound represented byformula (III):

where R₁ is an alkyl group or an aralkyl group; R₂ is hydrogen, an alkylgroup, an aralkyl group, ═O, —NH₂, —NHR, —N(R)₂, —NHC(O)R, —NRC(O)R,—NHC(O)R₅, or —NRC(O)R₅; R₃ and R₄ may be hydrogen or methyl, with theproviso that when R₃ is methyl then R₄ is hydrogen and when R₃ ishydrogen then R₄ is methyl; each R is, independently, an alkyl group, anaryl group, or an alkaryl group; and R₅ is

each X is, independently, halogen, —OH, —OR, an alkyl group, an arylgroup, —NH₂, —NHR, —N(R)₂, —CF₃, —CN, —C(O)NH₂, —C(O)NHR, or —C(O)N(R)₂;each R is, independently, an alkyl group, an aryl group, or an alkarylgroup; n is 0 or an integer from 1 to 5; and R_(a) is hydrogen or analkyl group, or a pharmaceutically acceptable salt thereof.
 12. Thecompound of claim 11, wherein R₁ is a C₁₋₈ alkyl group or an aryl-C₁₋₄alkyl group; R₃ is methyl; and R₄ is hydrogen.
 13. The compound of claim12, wherein R₁ is a C₁₋₈ alkyl group or an phenyl-C₁₋₄ alkyl group. 14.The compound of claim 11, wherein R₁ is a C₁₋₈ alkyl group or anaryl-C₁₋₄ alkyl group; R₃ is hydrogen; and R₄ is methyl.
 15. Thecompound of claim 14, wherein R, is a C₁₋₈ alkyl group or an phenyl-C₁₋₄alkyl group.
 16. The compound of claim 11, wherein R₂ is ═O.
 17. Acompound represented by formula (IV):

where R_(a) and R_(b) are each, independently, hydrogen or an alkylgroup, or R_(a) and R_(b), together, form a cycloalkyl group; each X is,independently, an alkyl group; ◯ is a five- or six-membered aryl orheteroaryl group; each Z is, independently, an alkyl group, —OH, —OR,halogen, —CF₃, —CN, —NH₂, —NHR, or —N(R)₂, wherein when Z is —N(R)₂ theR groups may, together, form a cyclic alkyl group; each R is,independently, an alkyl group, an aryl group, or an alkaryl group; eachW is an alkyl group; n is 0 or an integer from 1 to 4; y is 0 or aninteger from 1 to 5; z is 0 or an integer from 0 to 8; and R₅ is analkyl group, alkenyl group, or aralkyl group, or a pharmaceuticallyacceptable salt thereof.
 18. The compound of claim 17, wherein R_(a) andR_(b) are each, independently, hydrogen or a C₁₋₈ alkyl group, or R_(a)and R_(b), together, form a cycloalkyl group; each X is, independently,a C₁₋₈ alkyl group; ◯ is a five-membered heteroaryl group or asix-membered aryl or heteroaryl group; each W is a C₁₋₈ alkyl group; nis 0, 1 or 2; y is 0 an integer from 1 to 3; z is 0 an integer from 1 to4; and R₅ is a C₁₋₈ alkyl group, a C₃₋₈ alkenyl group, or an aryl-C₁₋₄alkyl group.
 19. The compound of claim 18, wherein ◯ is a five-memberedheteroaryl group containing up to 3 heteroatoms, a six-membered arylgroup or a six-membered heteroaryl group containing up to threeheteroatoms.
 20. The compound of claim 19, wherein the heteroatoms areeach, independently, nitrogen, oxygen or sulfur.
 21. The compound ofclaim 20, wherein R_(a) and R_(b) are each, independently, hydrogen or aC₁₋₄ alkyl group, or R_(a) and R_(b), together, form a cycloalkyl group;each X is, independently, a C₁₋₄ alkyl group; n is 0, 1 or 2; y is 0, 1or 2; z is 0 an integer from 1 to 4; and R₅ is a C₁₋₈ alkyl group, aC₃₋₈ alkenyl group, or a phenyl-C₁₋₄ alkyl group.
 22. The compound ofclaim 21, wherein ◯ is a six-membered aryl group; and z is an integerfrom 1 to
 4. 23. A method of binding opioid receptors, comprisingadministering an effective amount of the compound of claim 1 to amammalian subject in need thereof.
 24. A method of binding opioidreceptors, comprising administering an effective amount of the compoundof claim 6 to a mammalian subject in need thereof.
 25. A method ofbinding opioid receptors, comprising administering an effective amountof the compound of claim 11 to a mammalian subject in need thereof. 26.A method of binding opioid receptors, comprising administering aneffective amount of the compound of claim 17 to a mammalian subject inneed thereof.